Indoline derivatives substituted in the 6 position, their preparation and their use as medicaments

ABSTRACT

The present invention relates to indolinone derivatives, substituted in the 6-position, of the formula  
                 
in which 
     R 1  to R 6  and X are as defined in claim 1, to their tautomers, enantiomers, diastereomers, to their mixtures and to their salts, in particular their physiologically acceptable salts, which have useful pharmacological properties, in particular in inhibiting action on various receptor tyrosine kinases and on the proliferation of endothelial cells and various tumour cells, to medicaments comprising these compounds, to their use and to processes for their preparation.

RELATED APPLICATIONS

Benefit of U.S. Provisional Application Ser. No. 60/403,106, filed on Aug. 13, 2002, DE 10233366.1 filed Jul. 23, 2002, and DE 10328533.4, filed Jun. 24, 2003 are hereby claimed, and said applications are herein incorporated by reference.

The present invention relates to indolinone derivatives, substituted in the 6-position, of the formula

to their tautomers, enantiomers, diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts, which have useful pharmacological properties, to medicaments comprising these compounds to their use and to processes for their preparation.

The above compounds of the formula I have useful pharmacological properties, in particular an inhibition action on various kinases, especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3, PDGFRα, POGFRβ, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R and HGFR, Flt-3, and on the proliferation of cultivated human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular tumour cells.

Accordingly, the present invention provides the above compounds of the formula I, which have useful pharmacological properties, medicaments comprising these pharmacologically active compounds, their use and processes for their preparation. Moreover, the present invention provides the physiologically acceptable salts of the compounds according to the invention, medicaments comprising these compounds which in addition, if appropriate, contain one or more inert carrier materials and/or diluents, and their use for preparing a medicament suitable in particular for treating excessive or anormal cell proliferations.

The present invention furthermore provides processes for preparing this medicament, characterized in particular in that the compounds according to the invention or their physiologically acceptable salts are incorporated into one or more inert carrier materials and/or diluents.

I. In the above formula I,

-   -   X is an oxygen atom,     -   R¹ is a hydrogen atom,     -   R² is a fluorine, chlorine or bromine atom or a cyano group,     -   R³ is a phenyl group or a phenyl group which is monosubstituted         by a fluorine, chlorine, bromine or iodine atom or by a         C₁₋₃-alkoxy group, where the abovementioned unsubstituted and         the monosubstituted phenyl groups may additionally be         substituted in the 3- or 4-position         -   by a fluorine, chlorine or bromine atom,         -   by a cyano group,         -   by a C₁₋₃-alkoxy or C₁₋₂-alkyl-carbonyl-amino group,         -   by a cyano-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyl,             carboxy-C₁₋₄-alkoxy, carboxy-C₁₋₃-alkylamino,             carboxy-C₁₋₃-alkyl-N-(C₁₋₃-alkyl)-amino,             C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl,             C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy,             C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkylamino,             C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl-N-(C₁₋₃-alkyl)-amino,             amino-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,             (C₁₋₂-alkylamino)-carbonyl-C₁₋₃-alkyl,             di-(C₁₋₂-alkyl)-aminocarbonyl-C₁₋₃-alkyl,             (C₁₋₂-alkyl-carbonyl)-amino-C₁₋₃-alkyl,             (C₁₋₄-alkoxy-carbonyl)-amino-C₁₋₃-alkyl,             (C₃₋₆-alkyl-carbonyl)-amino-C₁₋₃-alkyl,             (phenyl-carbonyl)-amino-C₁₋₃-alkyl,             (C₃₋₆-cycloalkyl-carbonyl)-amino-C₁₋₃-alkyl,             (C₃₋₆-cycloalkyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,             (thiophen-2-yl-carbonyl)-amino-C₁₋₃-alkyl,             (furan-2-yl-carbonyl)-amino-C₁₋₃-alkyl,             (phenyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,             (2-(C₁₋₄-alkoxy)-benzoyl-carbonyl)-amino-C₁₋₃-alkyl,             (pyridin-2-yl-carbonyl)-amino-C₁₋₃-alkyl,             (pyridin-3-yl-carbonyl)-amino-C₁₋₃-alkyl-,             (pyridin-4-yl-carbonyl)-amino-C₁₋₃-alkyl- or             C₁₋₃-alkyl-piperazin-1-yl-carbonyl-C₁₋₃-alkyl group,         -   by a carboxy-C₂₋₃-alkenyl, aminocarbonyl-C₂₋₃-alkenyl,             (C₁₋₃-alkyl-amino)-carbonyl-C₂₋₃-alkenyl,             di-(C₁₋₃-alkyl)-amino-carbonyl-C₂₋₃-alkenyl or             C₁₋₄-alkoxy-carbonyl-C₂₋₃-alkenyl group,         -   where the substituents may be identical or different,     -   R⁴ is a phenyl group or a phenyl group which is monosubstituted         -   by a C₁₋₃-alkyl group which is terminally substituted by an             amino, guanidino, mono- or di-(C₁₋₂-alkyl)-amino-,             N-[ω-di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl]-N-(C₁₋₃-alkyl)-amino,             N-methyl-(C₃₋₄-alkyl)-amino, N-(C₁₋₃-alkyl)-N-benzylamino,             N-(C₁₋₄-alkoxycarbonyl)-amino,             N-(C₁₋₄-alkoxycarbonyl)-C₁₋₄-alkylamino,             4-(C₁₋₃-alkyl)-piperazin-1-yl, imidazol-1-yl,             pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl,             piperazin-1-yl, thiomorpholin-4-yl group,         -   by a di-(C₁₋₃-alkyl)-amino-(C₁₋₃-alkyl)-sulphonyl,             2-[di-(C₁₋₃-alkyl)-amino]-ethoxy,             4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,             {ω-[di-(C₁₋₃-alkyl)-amino]-(C₂₋₃-alkyl)}-N-(C₁₋₃-alkyl)-amino-carbonyl,             1-(C₁₋₃-alkyl)imidazol-2-yl, (C₁₋₃-alkyl)-sulphonyl group,             or         -   by a group of the formula         -   in which             -   R⁷ is a C₁₋₂-alkyl, C₁₋₂-alkyl-carbonyl,                 di-(C₁₋₂-alkyl)-amino-carbonyl-C₁₋₃-alkyl or                 C₁₋₃-alkylsulphonyl group and             -   R⁸ is C₁₋₃-alkyl, ω-[di-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl,                 ω-[mono-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl group, or             -   a (C₁₋₃-alkyl)-carbonyl, (C₄₋₆-alkyl)-carbonyl or                 carbonyl-(C₁₋₃-alkyl) group which is terminally                 substituted by a di-(C₁₋₂-alkyl)-amino, piperazin-1-yl                 or 4-(C₁₋₃-alkyl)-piperazin-1-yl group,     -   where all dialkylamino groups present in the radical R⁴ may also         be present in quaternized form, for example as an         N-methyl-(N,N-dialkyl)-ammonium group, where the counterion is         preferably selected from the group consisting of iodide,         chloride, bromide, methylsulphonate, para-toluenesulphonate and         trifluoroacetate,     -   R⁵ is a hydrogen atom and     -   R⁶ is a hydrogen atom,     -   where the abovementioned alkyl groups include linear and         branched alkyl groups in which additionally one to 3 hydrogen         atoms may be replaced by fluorine atoms,     -   where additionally a carboxyl, amino or imino group present may         be substituted by an in vivo cleavable radical or may be present         in the form of a prodrug radical, for example in the form of a         group which can be converted in vivo into a carboxyl group or in         the form of a group which can be converted in vivo into an imino         or amino group,     -   their tautomers, enantiomers, diastereomers, their mixtures and         their salts.         II. Particularly preferred compounds of the above formula I are         those compounds in which X, R¹, R⁵ and R⁶ are as defined         under I. and:

II.i. R² and R⁴ are as defined under I. and

R³ is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C₁₋₃-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or 4-position

-   -   by a fluorine, chlorine or bromine atom,     -   by a cyano group,     -   by a C₁₋₃-alkoxy or C₁₋₂-alkyl-carbonyl-amino group,     -   by a cyano-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyl, carboxy-C₁₋₄-alkoxy,         carboxy-C₁₋₃-alkylamino,         carboxy-C₁₋₃-alkyl-N-(C₁₋₃-alkyl)-amino,         C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl,         C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy,         C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkylamino,         C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl-N-(C₁₋₃-alkyl)-amino,         amino-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,         (C₁₋₂-alkylamino)-carbonyl-C₁₋₃-alkyl,         di-(C₁₋₂-alkyl)-aminocarbonyl-C₁₋₃-alkyl,         (C₁₋₂-alkyl-carbonyl)-amino-C₁₋₃-alkyl,         (C₁₋₄-alkoxy-carbonyl)-amino-C₁₋₃-alkyl,         (C₃₋₆-alkyl-carbonyl)-amino-C₁₋₃-alkyl,         (phenyl-carbonyl)-amino-C₁₋₃-alkyl,         (C₃₋₆-cycloalkyl-carbonyl)-amino-C₁₋₃-alkyl,         (C₃₋₆-cycloalkyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,         (thiophen-2-yl-carbonyl)-amino-C₁₋₃-alkyl,         (furan-2-yl-carbonyl)-amino-C₁₋₃-alkyl,         (phenyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,         (2-(C₁₋₄-alkoxy)-benzoyl-carbonyl)-amino-C₁₋₃-alkyl,         (pyridin-2-yl-carbonyl)-amino-C₁₋₃-alkyl,         (pyridin-3-yl-carbonyl)-amino-C₁₋₃-alkyl,         (pyridin-4-yl-carbonyl)-amino-C₁₋₃-alkyl or         C₁₋₃-alkyl-piperazin-1-yl-carbonyl-C₁₋₃-alkyl group,     -   by a carboxy-C₂₋₃-alkenyl, aminocarbonyl-C₂₋₃-alkenyl-,         (C₁₋₃-alkyl-amino)-carbonyl-C₂₋₃-alkenyl-,         di-(C₁₋₃-alkyl)-amino-carbonyl-C₂₋₃-alkenyl or         C₁₋₄-alkoxy-carbonyl-C₂₋₃-alkenyl group,     -   where the substituents may be identical or different;

II.ii. R² and R⁴ are as defined under I. and

R³ is a phenyl group which is substituted

-   -   by a C₁₋₂-alkyl-carbonyl-amino group,     -   by a carboxy-C₁₋₃-alkyl, carboxy-C₁₋₄-alkoxy,         C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl,         C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy, aminocarbonyl-C₁₋₃-alkyl,         (C₁₋₂-alkylamino)-carbonyl-C₁₋₃-alkyl,         di-(C₁₋₂-alkyl)-aminocarbonyl-C₁₋₃-alkyl,         (C₁₋₂-alkyl-carbonyl)-amino-C₁₋₃-alkyl,         (C₁₋₄-alkoxy-carbonyl)-amino-C₁₋₃-alkyl,         (phenyl-carbonyl)-amino-C₁₋₃-alkyl,         (C₃₋₆-cycloalkyl-carbonyl)-amino-C₁₋₃-alkyl,         (C₃₋₆-cycloalkyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,         (thiophen-2-yl-carbonyl)-amino-C₁₋₃-alkyl,         (furan-2-yl-carbonyl)-amino-C₁₋₃-alkyl,         (phenyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,         (2-(C₁₋₄-alkoxy)-benzoyl-carbonyl)-amino-C₁₋₃-alkyl,         (pyridin-2-yl-carbonyl)-amino-C₁₋₃-alkyl,         (pyridin-3-yl-carbonyl)-amino-C₁₋₃-alkyl,         (pyridin-4-yl-carbonyl)-amino-C₁₋₃-alkyl or         C₁₋₃-alkyl-piperazin-1-yl-carbonyl-C₁₋₃-alkyl group,     -   by an aminocarbonyl-C₂₋₃-alkenyl,         (C₁₋₃-alkylamino)-carbonyl-C₂₋₃-alkenyl,         di-(C₁₋₃-alkyl)-amino-carbonyl-C₂₋₃-alkenyl or         C₁₋₄-alkoxy-carbonyl-C₂₋₃-alkenyl group;

II.iii. R² and R⁴ are as defined under I. and

R³ is a phenyl group substituted by a carboxy-C₁₋₃-alkyl or C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl group;

II.iv. R³ and R⁴ are as defined under I. and

R² is a fluorine or chlorine atom;

II.v. R² and R³ are as defined under I. and

R⁴ is a phenyl group or a phenyl group which is monosubstituted

-   -   by a C₁₋₃-alkyl group which is terminally substituted by an         amino, guanidino, mono- or di-(C₁₋₂-alkyl)-amino-,         N-[ω-di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl]-N-(C₁₋₃-alkyl)-amino,         N-methyl-(C₃₋₄-alkyl)-amino, N-(C₁₋₃-alkyl)-N-benzylamino,         N-(C₁₋₄-alkoxycarbonyl)-amino,         N-(C₁₋₄-alkoxycarbonyl)-C₁₋₄-alkylamino,         4-(C₁₋₃-alkyl)-piperazin-1-yl, imidazol-1-yl, pyrrolidin-1-yl,         azetidin-1-yl, morpholin-4-yl, piperazin-1-yl,         thiomorpholin-4-yl group,     -   by a di-(C₁₋₃-alkyl)-amino-(C₁₋₃-alkyl)-sulphonyl,         2-[di-(C₁₋₃-alkyl)-amino]-ethoxy,         4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,         {ω-[di-(C₁₋₃-alkyl)-amino]-(C₂₋₃-alkyl)}-N-(C₁₋₃-alkyl)-amino-carbonyl,         1-(C₁₋₃-alkyl)imidazol-2-yl, (C₁₋₃-alkyl)-sulphonyl group, or     -   by a group of the formula     -   in which         -   R⁷ is a C₁₋₂-alkyl, C₁₋₂-alkyl-carbonyl,             di-(C₁₋₂-alkyl)-amino-carbonyl-C₁₋₃-alkyl or             C₁₋₃-alkylsulphonyl group and         -   R⁸ is C₁₋₃-alkyl, ω-[di-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl,             ω-[mono-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl group, or         -   a (C₁₋₃-alkyl)-carbonyl, (C₄₋₆-alkyl)-carbonyl or             carbonyl-(C₁₋₃-alkyl) group which is terminally substituted             by a di-(C₁₋₂-alkyl)-amino, piperazin-1-yl or             4-(C₁₋₃-alkyl)-piperazin-1-yl group,         -   where all dialkylamino groups present in the radical R⁴ may             also be present in quaternized form, for example as an             N-methyl-(N,N-dialkyl)-ammonium group, where the counterion             is preferably selected from the group consisting of iodide,             chloride, bromide, methylsulphonate, para-toluenesulphonate             and trifluoroacetate.             III. Subgroups of particularly preferred compounds of the             above formula I which are to be mentioned in particular are             those in which:

III.i. X, R¹, R², R⁵ and R⁶ are as defined under I., R³ is as defined under II.i. and R⁴ is as defined under II.v.;

III.ii. X, R¹, R², R⁵ and R⁶ are as defined under I., R³ is as defined under II.ii. and R⁴ is as defined under II.v.;

III.iii. X, R¹, R², R⁵ and R⁶ are as defined under I., R³ is as defined under II.iii. and R⁴ is as defined under II.v.;

III.iv. X, R¹, R⁵ and R⁶ are as defined under I., R² is as defined under II.iv., R³ is as defined under II.i., II.ii. or II.iii. and R⁴ is as defined under II.v.

A further preferred group of compounds of the above formula I are those in which

-   X is an oxygen atom, -   R¹ is a hydrogen atom, -   R² is a fluorine, chlorine or bromine atom or a cyano group, -   R³ is a phenyl group or a phenyl group which is monosubstituted by a     fluorine, chlorine, bromine or iodine atom or by a C₁₋₃-alkoxy     group, where the abovementioned unsubstituted and the     monosubstituted phenyl groups may additionally be substituted in the     3- or 4-position     -   by a fluorine, chlorine or bromine atom,     -   by a C₁₋₃-alkoxy or C₁₋₂-alkyl-carbonyl-amino group,     -   by a carboxy-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,         (C₁₋₂-alkylamino)-carbonyl-C₁₋₃-alkyl,         di-(C₁₋₂-alkyl)-aminocarbonyl-C₁₋₃-alkyl,         (C₁₋₂-alkyl-carbonyl)-amino-C₁₋₃-alkyl or         (phenyl-carbonyl)-amino-C₁₋₃-alkyl group,     -   where the substituents may be identical or different, -   R⁴ is a phenyl group which is substituted     -   by a C₁₋₃-alkyl group terminally substituted by a         di-(C₁₋₂-alkyl)-amino group, or     -   by a group of the formula     -   in which         -   R⁷ is a C₁₋₂-alkyl, C₁₋₂-alkyl-carbonyl,             di-(C₁₋₂-alkyl)-amino-carbonyl-C₁₋₃-alkyl or             C₁₋₃-alkylsulphonyl group and         -   R⁸ is a C₁₋₃-alkyl or ω-[di-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl             group, or         -   a C₁₋₃-alkyl-carbonyl group terminally substituted by a             di-(C₁₋₂-alkyl)-amino, piperazino or             4-(C₁₋₃-alkyl)-piperazin-1-yl group, -   R⁵ is a hydrogen atom and -   R⁶ is a hydrogen atom, -   where the abovementioned alkyl groups include linear and branched     alkyl groups in which additionally one to 3 hydrogen atoms may be     replaced by fluorine atoms, -   where additionally a carboxyl, amino or imino group present may be     substituted by an in vivo cleavable radical, -   their tautomers, enantiomers, diastereomers, their mixtures and     their salts.

The following compounds of the formula I are particularly preferred:

-   (a)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (b)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (c)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (d)     3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (e)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (f)     3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (g)     3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (h)     3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (i)     3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (j)     3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (k)     3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (l)     3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (m)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (n)     3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (O)     3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (p)     3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (q)     3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone     where additionally a carboxyl, amino or imino group present may be     substituted by an in vivo cleavable radical or may be present in the     form of a prodrug radical, for example in the form of a group which     can be converted in vivo into a carboxyl group or in the form of a     group which can be converted in vivo into an imino or amino group,     and their salts.

A group which can be converted in vivo into a carboxyl group is to be understood as meaning, for example, a hydroxymethyl group, a carboxyl group which is esterified with an alcohol in which the alcoholic moiety is preferably a C₁₋₆-alkanol, a phenyl-C₁₋₃-alkanol, a C₃₋₉-cycloalkanol, where a C₅₋₈-cycloalkanol may additionally be substitituted by one or two C₁₋₃-alkyl groups, a C₅₋₈-cycloalkanol in which one methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkoxy-carbonyl or C₁₋₆-alkyl-carbonyl group and in which the cycloalkanol moiety may additionally be substituted by one or two C₁₋₃-alkyl groups, a C₄₋₇-cycloalkenol, a C₃₋₅-alkenol, a phenyl-C₃₋₅-alkenol, a C₃₋₅-alkynol or a phenyl-C₃₋₅-alkynol, with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C₃₋₈-cycloalkyl-C₁₋₃-alkanol, a bicycloalkanol having a total of 8 to 10 carbon atoms which may additionally be substituted in the bicycloalkyl moiety by one or two C₁₋₃-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of the formula R_(a)—CO—O—(R_(b)CR_(c))—OH,

-   -   in which     -   R_(a) is a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl or         phenyl-C₁₋₃-alkyl group,     -   R_(b) is a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or         phenyl group, and     -   R_(c) is a hydrogen atom or a C₁₋₃-alkyl group,         and a radical cleavable in vivo from an imino or amino group is         to be understood as meaning, for example, a hydroxyl group, an         acyl group, such as the benzoyl or pyridinoyl group, or a         C₁₋₁₆-alkylcarbonyl group, such as the formyl, acetyl,         propionyl, butanoyl, pentanoyl or hexanoyl group, an         allyloxycarbonyl group, a C₁₋₁₆-alkoxy-carbonyl group, such as         the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,         isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,         pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl,         nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl,         dodecyloxycarbonyl or hexadecyloxycarbonyl group, a         phenyl-C₁₋₆-alkoxy-carbonyl group, such as the         benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl         group, a C₁₋₃-alkylsulphonyl-C₁₋₄-alkoxy-carbonyl,         C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxy-carbonyl or         R_(a)CO—O—(R_(b)CR_(c))—O—CO— group, in which     -   R_(a) is a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl or         phenyl-C₁₋₃-alkyl group,     -   R_(b) is a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or         phenyl group and     -   R_(c) is a hydrogen atom, a C₁₋₃-alkyl or         R_(a)CO—O—(R_(b)CR_(c))—O— group, in which R_(a) to R_(c) are as         defined above,         and additionally, for an amino group, the phthalimido group,         where the ester radicals mentioned above can also be used as a         group which can be converted in vivo into a carboxyl group.

Preferred prodrug radicals for a carboxyl group are a C₁₋₆-alkoxy-carbonyl group, such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl group, or a phenyl-C₁₋₃-alkoxy-carbonyl group, such as the benzyloxycarbonyl group, and,

for an imino or amino group, a C₁₋₉-alkoxy-carbonyl group, such as the methoxy-carbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxy-carbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl group, a phenyl-C₁₋₃-alkoxy-carbonyl group, such as the benzyloxycarbonyl group, a phenylcarbonyl group optionally substituted by a C₁₋₃-alkyl group, such as the benzoyl or 4-ethyl-benzoyl group, a pyridinoyl group, such as the nicotinoyl group, a C₁₋₃-alkylsulphonyl-n-C₂₋₃-alkoxy-carbonyl or C₁₋₃-alkoxy-C₂₋₃-alkoxy-C₁₋₄-alkoxy-carbonyl group, such as the 2-methylsulphonylethoxycarbonyl or 2-(2-ethoxy)-ethoxycarbonyl group.

According to the invention, the novel compounds are obtained, for example, by the following processes, which are known in principle from the literature: a. reaction of a compound of the formula

in which

-   -   the radicals Z¹ and R³ may, if appropriate, change their         positions,     -   X, R², R³ and R⁶ are as defined at the outset,     -   R^(1,) has the meanings mentioned at the outset for R¹ or is a         protective group for the nitrogen atom of the lactam group,         where R¹ may also, if appropriate, represent a bond, formed via         a spacer, to a solid phase,     -   and Z¹ is a halogen atom, a hydroxyl, alkoxy or arylalkoxy         group, for example a chlorine or bromine atom, a methoxy, ethoxy         or benzyloxy group,     -   with an amine of the formula         in which     -   R⁴ and R⁵ are defined as mentioned at the outset,     -   and, if required, the product is subsequently cleaved from a         protective group used for the nitrogen atom of the lactam group         or from a solid phase.

Suitable protective groups for the nitrogen atom of the lactam group are, for example, an acetyl, benzoyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl group and

suitable solid phases are a resin, such as a 4-(2′,4′-dimethoxyphenylaminomethyl)-phenoxy resin, where the attachment is expediently via the amino group, or a p-benzyloxybenzyl alcohol resin, where the attachment is expediently via a spacer, such as a 2,5-dimethoxy-4-hydroxybenzyl derivative.

The reaction is expediently carried out in a solvent, such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethyl sulphoxide, methylene chloride or a mixture thereof, if appropriate in the presence of an inert base, such as triethylamine, N-ethyldiisopropylamine or sodium bicarbonate, at temperatures between 20 and 175° C., where any protective groups used may be simultaneously removed owing to transamidation.

If, in a compound of the formula V, Z¹ is a halogen atom, the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120° C.

If, in a compound of the formula V, Z¹ is a hydroxyl, alkoxy or arylalkoxy group, the reaction is preferably carried out at temperatures between 20 and 200° C.

The subsequent removal of a protective group used, which may be required, if appropriate, is expediently carried out either hydrolytically in an aqueous or alcoholic solvent, for example in methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxane/water, dimethylformamide/water, methanol or ethanol, in the presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.,

or, advantageously, by transamidation with an organic base, such as ammonia, butylamine, dimethylamine or piperidine, in a solvent, such as methanol, ethanol, dimethylformamide and mixtures thereof, or in an excess of the amine used, at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.

Cleavage from a solid phase employed is preferably carried out using trifluoroacetic acid and water at temperatures between 0 and 35° C., preferably at room temperature.

b. To prepare a compound of the formula I in which R³ is a phenyl or naphthyl group substituted by a carboxy-C₂₋₃-alkenyl, aminocarbonyl-C₂₋₃-alkenyl, (C₁₋₃-alkylamino)-carbonyl-C₂₋₃-alkenyl, di-(C₁₋₃-alkylamino)-carbonyl-C₂₋₃-alkenyl or C₁₋₄-alkoxy-carbonyl-C₂₋₃-alkenyl group, reaction of a compound of the formula

in which

-   -   R², R⁴, R⁵, R⁶ and X are as defined at the outset,     -   R¹′ has the meanings mentioned at the outset for R¹ or is a         protective group for the nitrogen atom of the lactam group,         where R¹ may also, if appropriate, represent a bond, formed via         a spacer, to a solid phase, and     -   Z³ is a leaving group, for example a halogen atom or an alkyl-         or arylsulphonyloxy group, such as a chlorine, bromine or iodine         atom or a methylsulphonyloxy, ethylsulphonyloxy,         p-toluenesulphonyloxy or trifluoromethanesulphonyloxy group,         with an alkene of the formula         in which     -   R^(3,) is an amino, (C₁₋₃-alkylamino), di-(C₁₋₃-alkylamino) or         C₁₋₄-alkoxy group and n is the number 0 or 1.

The reaction is expediently carried out with palladium catalysis, using, for example, palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(II) acetate, bis(triphenylphosphine)palladium(II) chloride, palladium/carbon, bis-[1,2-bis(diphenylphosphino)ethane]palladium(0), dichloro-(1,2-bis(diphenylphosphino)-ethane)palladium(II), tetrakistriphenylphosphinepalladium(0), tris(dibenzylideneacetone)dipalladium(0), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) or tris(dibenzylideneacetone)dipalladium(0)/chloroform adduct, in the presence of a base, such as triethylamine, diisopropylethylamine, lithium carbonate, potassium carbonate, sodium carbonate, caesium carbonate, and a ligand, such as triphenylphosphine, tri-ortho-tolylphosphine or tri-(tert-butyl)phosphine, in solvents such as acetonitrile, N-methylpyrrolidinone, dioxane or dimethylformamide and mixtures thereof.

The cleavage of a protective group used for the nitrogen atoms of the lactam group or from a solid phase, which may be required, if appropriate, is carried out as described above under process (a).

c. To prepare a compound of the formula I in which R³ is a phenyl or naphthyl group substituted by

-   -   a carboxy-C₁₋₃-alkyl, C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl,         aminocarbonyl-C₁₋₃-alkyl, (C₁₋₃-alkylamino)-carbonyl-C₁₋₃-alkyl         or di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl group,         hydrogenation of a compound of the formula         in which     -   R², R⁴, R⁵, R⁶ and X are as defined at the outset,     -   R^(1,) has the meanings mentioned at the outset for R¹ or is a         protective group for the nitrogen atom of the lactam group,         where R^(1,) may also, if appropriate, represent a bond, formed         via a spacer, to a solid phase,     -   A is a C₂₋₃-alkenyl group and     -   R³ is a hydroxyl, C₁₋₄-alkoxy, amino, (C₁₋₃-alkylamino) or         di-(C₁₋₃-alkyl)amino group.

The hydrogenation is preferably carried out using catalytic hydrogenation with hydrogen in the presence of a catalyst, such as palladium/carbon or platinum, in a solvent, such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with addition of an acid, such as hydrochloric acid, at temperatures between 0 and 50° C., but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.

The cleavage of a protective group used for the nitrogen atom of the lactam group or from a solid phase, which may be required, if appropriate, is carried out as described under process (a).

If, according to the invention, a compound of the formula I is obtained which contains an alkoxycarbonyl group, this can be converted by hydrolysis into a corresponding carboxyl compound, or

-   -   if a compound of the formula I is obtained which contains an         amino or alkylamino group, this can be converted by reduction         alkylation into a corresponding alkylamino or dialkylamino         compound, or     -   if a compound of the formula I is obtained which contains a         dialkylamino group, this can be converted by alkylation into a         corresponding trialkylammonium compound, or     -   if a compound of the formula I is obtained which contains an         amino or alkylamino group, this can be converted by acylation or         sulphonation into a corresponding acyl or sulphonyl compound,         respectively, or     -   if a compound of the formula I is obtained which contains a         carboxyl group, this can be converted by esterification or         amidation into a corresponding ester or aminocarbonyl compound,         respectively, or     -   if a compound of the formula I is obtained which contains a         nitro group, this can be converted by reduction into a         corresponding amino compound, or     -   if a compound of the formula I is obtained which contains a         cyano group, this can be converted by reduction into a         corresponding aminomethyl compound, or     -   if a compound of the formula I is obtained which contains an         arylalkyloxy group, this can be converted with acid into a         corresponding hydroxyl compound, or     -   if a compound of the formula I is obtained which contains an         alkoxycarbonyl group, this can be converted by hydrolysis into a         corresponding carboxyl compound, or     -   if a compound of the formula I is obtained in which R₄ is a         phenyl group substituted by an amino, alkylamino, aminoalkyl or         N-alkylamino group, this can then be converted by reaction with         a corresponding cyanate, isocyanate or carbamoyl halide into a         corresponding urea compound of the formula I, or     -   if a compound of the formula I is obtained in which R₄ is a         phenyl group substituted by an amino, alkylamino, aminoalkyl or         N-alkylamino group, this can subsequently be converted by         reaction with a corresponding amidino-group-transferring         compound or by reaction with a corresponding nitrile into a         corresponding guanidino compound of the formula I.

The subsequent hydrolysis is preferably carried out in an aqueous solvent, for example in water, methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as trifluoroacetic acid, hydrochloric acid or sulphuric acid, or in the presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.

The subsequent reductive alkylation is preferably carried out in a suitable solvent, such as methanol, methanol/water, methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, if appropriate with addition of an acid, such as hydrochloric acid, in the presence of catalytically activated hydrogen, for example of hydrogen in the presence of Raney nickel, platinum or palladium/carbon, or in the presence of a metal hydride, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride or lithium aluminium hydride, at temperatures between 0 and 100° C., preferably at temperatures between 20 and 80° C.

The subsequent alkylation is preferably carried out in a suitable solvent, such as ether, tetrahydrofuran, dioxane, dichloromethane, acetone or acetonitrile, in the presence of alkylating agents, such as alkyl iodides, alkyl bromides, alkyl chlorides, methanesulphonic acid alkyl esters, para-toluenesulphonic acid alkyl esters or alkyl trifluoroacetates, at temperatures between 0 and 100° C., preferably at temperatures between 20 and 60° C.

The subsequent acylation or sulphonylation is expediently carried out using the corresponding free acid or a corresponding reactive compound, such as its anhydride, ester, imidazolide or halide, preferably in a solvent, such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulphoxide or dimethylformamide, if appropriate in the presence of an inorganic or a tertiary organic base, at temperatures between −20 and 200° C., preferably at temperatures between 20° C. and the boiling point of the solvent used. The reaction with the free acid can, if appropriate, be carried out in the presence of an agent which activates the acid or of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N′-dicyclohexylcarbodiimide, N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N′-dicyclohexyl-carbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxybenzotriazole, N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and, if appropriate, with addition of a base, such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, expediently at temperatures between 0 and 150° C., preferably at temperatures between 0 and 100° C. The reaction with a corresponding reactive compound can, if appropriate, be carried out in the presence of a tertiary organic base, such as triethylamine, N-ethyl-diisopropylamine, N-methylmorpholine or pyridine, or, if an anhydride is used, in the presence of the corresponding acids, at temperatures between 0 and 150° C., preferably at temperatures between 50 and 100° C.

The subsequent esterification or amidation is expediently carried out by reacting a reactive corresponding carboxylic acid derivative with an appropriate alcohol or amine, as described above.

The esterification or amidation is preferably carried out in a solvent, such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulphoxide or dimethylformamide, if appropriate in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20° C. and the boiling point of the solvent used. Here, the reaction with a corresponding acid is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N′-dicyclohexylcarbodiimide, N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N′-dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxybenzotriazole, N,N′-carbonyldiimidazole or triphenyl-phosphine/carbon tetrachloride, and, if appropriate, with addition of a base, such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, expediently at temperatures between 0 and 150° C., preferably at temperatures between 0 and 100° C., and the acylation with a corresponding reactive compound, such as its anhydride, ester, imidazolide or halide, is, if appropriate, carried out in the presence of a tertiary organic base, such triethylamine, N-ethyldiisopropylamine or N-methylmorpholine, at temperatures between 0 and 150° C., preferably at temperatures between 50 and 100° C.

The subsequent reduction of a nitro group is preferably carried out hydrogenolytically, for example with hydrogen in the presence of a catalyst, such as palladium/carbon or Raney nickel, in a solvent, such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with addition of an acid, such as hydrochloric acid or glacial acetic acid, at temperatures between 0 and 50° C., but preferably at room temperature, and at a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar.

The subsequent hydrogenation of a cyano group is preferably carried out hydrogenolytically, for example using hydrogen in the presence of a catalyst, such as palladium/carbon or Raney nickel, in a solvent, such as methanol, ethanol, ethyl acetate, methylene chloride, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with addition of an acid, such as hydrochloric acid or glacial acetic acid, at temperatures between 0 and 50° C., but preferably at room temperature, and at a hydrogen pressure of from 1 to 7 bar, but preferably of from 3 to 5 bar.

The subsequent preparation of a corresponding guanidino compound of the formula I is expediently carried out by reaction with an amidino-group-transferring compound, such as 3,5-dimethylpyrazole-1-carboxamidine, preferably in a solvent, such as dimethylformamide, and, if appropriate, in the presence of a tertiary organic base, such as triethylamine, at temperatures between 0 and 50° C., preferably at room temperature.

In the reactions described above, any reactive groups present, such as carboxyl, hydroxyl, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are removed again after the reaction.

A protective radical for a carboxyl group is, for example, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, and

-   -   a protective group for a hydroxyl, amino, alkylamino or imino         group is, for example, the acetyl, trifluoroacetyl, benzoyl,         ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl,         methoxybenzyl or 2,4-dimethoxybenzyl group, and, for the amino         group, additionally the phthalyl group.

The subsequent removal of a protective radical used is, if appropriate, carried out, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as trifluoroacetic acid, hydrochloric acid or sulphuric acid, or in the presence of an alkali metal base, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical is removed, for example, hydrogenolytically, for example using hydrogen in the presence of a catalyst, such as palladium/carbon, in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with addition of an acid, such as hydrochloric acid or glacial acetic acid, at temperatures between 0 and 50° C., but preferably at room temperature, and at a hydrogen pressure of from 1 to 7 bar, but preferably of from 3 to 5 bar.

A methoxybenzyl group can also be removed in the presence of an oxidizing agent, such as cerium(IV) ammonium nitrate, in a solvent, such as methylene chloride, acetonitrile or acetonitrile/water, at temperatures between 0 and 50° C., but preferably at room temperature.

However, a 2,4-dimethoxybenzyl radical is preferably removed in trifluoroacetic acid in the presence of anisole.

A tert-butyl or tert-butyloxycarbonyl radical is preferably removed by treatment with an acid, such as trifluoroacetic acid or hydrochloric acid, using, if appropriate, a solvent, such as methylene chloride, dioxane, ethyl acetate or ether.

A phthalyl radical is preferably removed in the presence of hydrazine or a primary amine, such as methylamine, ethylamine or n-butylamine, in a solvent, such as methanol, ethanol, isopropanol, toluene/water or dioxane, at temperatures between 20 and 50° C.

Furthermore, chiral compounds of the formula I obtained can be separated into their enantiomers and/or diastereomers.

Thus, for example, compounds of the formula I obtained which occur as racemates can be separated by methods known per se (see Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their enantiomers, and compounds of the formula I having at least 2 asymmetric carbon atoms can, owing to their physicochemical differences, be separated by methods known per se, for example by chromatography and/or fractional crystallization, into their diastereomers, which, if they are obtained in racemic form, can then be separated into the enantiomers as mentioned above.

The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as, for example, esters or amides, with the racemic compound, in particular acids and their activated derivatives or alcohols, and separating the mixture of diastereomeric salts or derivatives obtained in this manner, for example owing to different solubilities, whereupon the free enantiomers can be released from the pure diastereomeric salts or derivatives by action of suitable agents. Particularly common optically active acids are, for example, the D and L forms of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-acetylaspartic acid or quinic acid. A suitable optically active alcohol is, for example, (+)- or (−)-menthol, and a suitable optically active acyl radical in amides is, for example, the (+)- or (−)-menthyloxycarbonyl radical.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular, for pharmaceutical use, into their physiologically acceptable salts, with inorganic or organic acids. Acids suitable for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, methanesulphonic acid, ethanesulphonic acid, para-toluenesulphonic acid, phenylsulphonic acid or L-(+)-mandelic acid.

Moreover, the resulting novel compounds of the formula I can, if they contain a carboxyl group, then, if desired, be converted into their salts with inorganic or organic bases, in particular, for pharmaceutical use, into their physiologically acceptable salts. Bases suitable for this purpose are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Also suitable, for compounds of the formula I which contain 2 or more acidic or basic groups, are salts with 2 or more inorganic or organic bases or acids (disalts etc.).

Some of the compounds of the general formulae V to XI used as starting materials are known from the literature or can be obtained by processes known from the literature or can be obtained by the processes described above and in the examples. Compounds of the general formula IX, for example, are described in the German patent application 198 44 003.

As already mentioned at the outset, the novel compounds of the formula (I) have useful pharmacological properties, in particular in inhibiting action on various kinases, especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3, PDGFRα, PDGFRβ, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R and HGFR, Flt-3, and on the proliferation of cultivated human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular of tumour cells.

The biological properties of the novel compounds were examined by the following standard methods:

Human umbilical cord endothelial cells (HUVEC) were cultivated in IMDM (Gibco BRL), supplemented with 10% foetal bovine serum (FBS) (Sigma), 50 μM β-mercaptoethanol (Fluka), standard antibiotics, 15 μg/ml of endothelial cell growth factor (ECGS, Collaborative Biomedical Products) and 100 μg/ml of heparin (Sigma) on gelatin-coated culture bottles (0.2% gelatin, Sigma) at 37° C., 5% CO₂, in an atmosphere saturated with water.

To examine the inhibitory activity of the compounds according to the invention, the cells were “starved” for 16 hours, i.e. kept in culture medium without growth factors (ECGS+heparin). Using trypsin/EDTA, the cells were detached from the culture bottles and washed once with serum-containing medium. 2.5×10³ cells were then seeded in each well.

The proliferation of the cells was stimulated using 5 ng/ml of VEGF₁₆₅ (vascular endothelial growth factor; H. Weich, GBF Brunswick) and 10 μg/ml of heparin. Per plate, as control value, in each case 6 wells were not stimulated.

The compounds according to the invention were dissolved in 100% dimethyl sulphoxide and, in triplicate, added to the cultures in different dilutions, the maximum dimethyl sulphoxide concentration being 0.3%.

The cells were incubated at 37° C. for 76 hours, and ³H-thymidine (0.1 μCi/well, Amersham) was then added for a further 16 hours to determine DNA synthesis. The radioactively labelled cells were then immobilized on filter mats and the incorporated radioactivity was determined in a β counter. To determine the inhibitory activity of the compounds according to the invention, the mean value for the non-stimulated cells was subtracted from the mean value of the factor-stimulated cells (in the presence or absence of the compounds according to the invention).

The relative cell proliferation was calculated in percent of the control (HUVEC without inhibitor), and the concentration of active compound at which the proliferation of the cells is inhibited by 50% (IC₅₀) was derived therefrom.

The compounds of the formula I according to the invention have an IC₅₀ between 50 μM and 1 nM.

Owing to their inhibitory action on the proliferation of cells, in particular of endothelian cells and of tumour cells, the compounds of the formula I are suitable for treating diseases in which the proliferation of cells, in particular that of endothelial cells, plays a role.

Thus, for example, the proliferation of endothelial cells and the related neovascularization is a decisive step in tumour progression (Folkman J. et al., Nature 339, 58-61, (1989); Hanahan D. and Folkman J., Cell 86, 353-365, (1996)). Furthermore, the proliferation of endothelial cells is also of importance in haemangiomes, in metastasization, in rheumatoid arthritis, in psoriasis and in ocular neovascularization (Folkman J., Nature Med. 1, 27-31, (1995); Carmeliet P & Rakeh J., Nature 407, 249-257, (2000)). The therapeutic benefit of inhibitors of endothelial cell proliferation in the animal model was shown, for example, by O'Reilly et al. and Parangi et al. (O'Reilly M. S. et al., Cell 88, 277-285, (1997); Parangi S. et al., Proc Natl Acad Sci USA 93, 2002-2007, (1996)).

Thus, the compounds of the formula I, their tautomers, their stereoisomers or their physiologically acceptable salts are suitable, for example, for treating tumours (for example squamous epithelium carcinoma, astrocytoma, Kaposi sarcoma, glioblastoma, lung cancer, cancer of the bladder, neck carcinoma, oesophagus carcinoma, melanoma, ovarial carcinoma, prostate carcinoma, breast cancer, small-cell lung carcinoma, glioma, colorectal carcinoma, pancreas carcinoma, urogenital cancer and gastrointestinal carcinoma, and also haematological cancers, such as, for example, multiple myeloma and acute myelotic leukaemia), psoriasis, arthritis (for example rheumatoid arthritis), haemangioma, angiofibroma, disorders of the eye (for example diabetic retinopathy), neovascular glaucoma, disorders of the kidneys (for example glomerulonephritis), diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndromes, transplantation rejections and glomerulopathy, fibrotic disorders (for example cirrhosis of the liver), mesangial-cell-proliferative disorders, atherosclerosis, injuries of the nerve tissue and for inhibiting the reocclusion of vessels after balloon catheter treatment, in vessel prosthetics or after implantation of mechanical devices for keeping vessels open (for example stents) or other disorders in which cell proliferation or angiogenesis play a role. Owing to their biological properties, the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumour therapy in monotherapy or in combination with other antitumor therapeutics, for example in combination with topoisomerase inhibitors (for example etoposide), mitosis inhibitors (for example vinblastine, Taxol), compounds which interact with nucleic acids (for example cisplatin, cyclophosphamide, adriamycin), hormone antagonists (for example tamoxifen), steroids and analogues thereof (for example dexamethasone), inhibitors of metabolic processes (for example 5-FU etc.), cytokines (for example interferons), kinase inhibitors (for example EGFR kinase inhibitoren, such as, for example, Iressa; Gleevec), allosterically acting receptor tyrosine kinase inhibitors, antibodies (for example Herceptin), COX-2 inhibitors or else in combination with radiotherapy, etc. These combinations can be administered either simultaneously or sequentially.

The invention is illustrated in more detail by the examples below: Example Name 1.0 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-iodophenyl)- methylene]-6-chloro-2-indolinone 1.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-iodophenyl)methylene]-6- chloro-2-indolinone 1.2 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1- (4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.3 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4- chlorophenyl)methylene]-6-chloro-2-indolinone 1.4 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2- indolinone 1.5 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4- chlorophenyl)methylene]-6-chloro-2-indolinone 1.6 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-chlorophenyl)methylene]- 6-chloro-2-indolinone 1.7 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3,4- dimethoxyphenyl)methylene]-6-chloro-2-indolinone 1.8 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2- indolinone 1.9 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 1.10 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)- methylene]-6-chloro-2-indolinone 1.11 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylcarbamoyl)anilino)-1-(3,4- dimethoxyphenyl)methylene]-6-chloro-2-indolinone 2.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-cyanophenyl)-methylene]- 6-chloro-2-indolinone 3.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-iodophenyl)methylene]-6- fluoro-2-indolinone 3.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-fluorophenyl)methylene]- 6-fluoro-2-indolinone 3.2 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3- fluorophenyl)methylene]-6-fluoro-2-indolinone 3.3 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-fluorophenyl)methylene]-6-fluoro-2- indolinone 3.4 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2- acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.5 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2- acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.6 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6- fluoro-2-indolinone 3.7 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.8 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-iodophenyl)methylene]-6- fluoro-2-indolinone 3.9 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.10 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl- aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.11 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.12 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6- fluoro-2-indolinone 3.13 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-cyanomethylphenyl)- methylene]-6-fluoro-2-indolinone 3.14 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-(N-tert-butoxycarbonyl- aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.15 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(N-tert-butoxycarbonyl- aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.16 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-2- aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.17 3-Z-[1-(4-(N-Acetyl-N-methylamino)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.18 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]- 6-fluoro-2-indolinone 3.19 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.20 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.21 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.22 3-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.23 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.24 3-Z-[1-(4-methylsulphonylanilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.25 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6- fluoro-2-indolinone 3.26 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.27 3-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl)anilino)-1-(3- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.28 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1- (3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.29 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.30 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.31 3-Z-[1-(4-(N-(4-dimethylamino-butylcarbonyl)-N-methylamino)anilino)- 1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.32 3-Z-[1-Anilino-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro- 2-indolinone 3.33 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.34 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.35 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N- methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)- methylene]-6-fluoro-2-indolinone 3.36 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1- (4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.37 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.38 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1- (4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.39 3-Z-[1-(4-methylsulphonylanilino)-1-(4- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.40 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)- 1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.41 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.42 3-Z-[1-Anilino-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro- 2-indolinone 3.43 3-Z-[1-(4-methylsulphonylanilino)-1-(3-methoxycarbonylmethylphenyl)- methylene]-6-fluoro-2-indolinone 3.44 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.45 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N- methylsulphonylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)- methylene]-6-fluoro-2-indolinone 3.46 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)- 1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.47 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1- (3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.48 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]- 6-fluoro-2-indolinone 3.49 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.50 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1- (3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.51 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.52 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-(N-tert-butoxycarbonyl- aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.53 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3- acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.54 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3- acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.55 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.56 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1- (3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.57 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.58 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1- (4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.59 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1- (4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.60 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2- ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.61 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.62 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)- 1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.63 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1- (3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.64 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2- ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.65 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1- (4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.66 3-Z-[1anilino-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro- 2-indolinone 3.67 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.68 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.69 3-Z-[1-(4-(N-tert-butoxycarbonylaminomethyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.70 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.71 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4- methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.72 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2- ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.73 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.74 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2- ethoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.75 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.76 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2- ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.77 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.78 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.79 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.80 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.81 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1- (4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.82 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1- (3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.83 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.84 3-Z-[1anilino-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2- indolinone 3.85 3-Z-[1-(4-(N-tert-butoxycarbonylaminomethyl)anilino)-1-(3-(2- ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.86 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(3-(2- ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.87 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-methoxycarbonylmethoxy- phenyl)methylene]-6-fluoro-2-indolinone 3.88 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-methoxycarbonylmethoxy- phenyl)methylene]-6-fluoro-2-indolinone 3.89 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-ethoxycarbonyl- ethoxy)phenyl)methylene]-6-fluoro-2-indolinone 3.90 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.91 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.92 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.93 3-Z-[1-(3-dimethylaminomethylanilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.94 3-Z-[1-(3-dimethylaminomethylanilino)-1-(3-(2- ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.95 3-Z-[1-(3-dimethylaminomethylanilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 4.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)- methylene]-6-cyano-2-indolinone 5.0 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2- methoxycarbonylvinyl)phenyl)methylene]-6-chloro-2-indolinone 5.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonyl- vinyl)phenyl)methylene]-6-chloro-2-indolinone 5.2 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carbamoyl- vinyl)phenyl)methylene]-6-fluoro-2-indolinone 5.3 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonyl- vinyl)phenyl)methylene]-6-fluoro-2-indolinone 5.4 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-methoxycarbonyl- vinyl)phenyl)methylene]-6-fluoro-2-indolinone 6.0 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 6.1 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2- methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 6.2 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carbamoyl- ethyl)phenyl)methylene]-6-fluoro-2-indolinone 6.3 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 6.4 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 7.0 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-aminomethylphenyl)- methylene]-6-chloro-2-indolinone 8.0 3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N- methylamino)anilino)-1-(4-aminomethylphenyl)methylene]-6-chloro-2- indolinone 9.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-aminomethylphenyl)- methylene]-6-fluoro-2-indolinone 9.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2- aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.2 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-aminomethylphenyl)- methylene]-6-fluoro-2-indolinone 9.3 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-aminomethylphenyl)methylene]-6-fluoro-2- indolinone 9.4 3-Z-[1-(4-(methylaminomethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.5 3-Z-[1-(4-(methylaminomethyl)anilino)-1-(4-(2-methylcarbamoyl- ethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.6 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-aminomethylphenyl)methylene]-6-fluoro-2- indolinone 9.7 3-Z-[1-(4-(aminomethyl)anilino)-1-(4-(2- methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.8 3-Z-[1-(4-(aminomethyl)anilino)-1-(3-(2- ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.9 3-Z-[1-(4-(methylaminomethyl)anilino)-1-(3-(2- ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.0 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.1 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.2 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylphenyl)- methylene]-6-fluoro-2-indolinone 10.3 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.4 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylphenyl)- methylene]-6-fluoro-2-indolinone 10.5 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2- indolinone 10.6 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.7 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.8 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro- 2-indolinone 10.9 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.10 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.11 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.12 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.13 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.14 3-Z-[1-(4-methylsulphonylanilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.15 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3- carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.16 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2- indolinone 10.17 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1- (3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.18 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1- (3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.19 3-Z-[1-Anilino-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2- indolinone 10.20 3-Z-[1-(4-methylsulphonylanilino)-1-(3-carboxymethylphenyl)- methylene]-6-fluoro-2-indolinone 10.21 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-carboxymethylphenyl)- methylene]-6-fluoro-2-indolinone 10.22 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N- methylsulphonylamino)anilino)-1-(3-carboxymethylphenyl)-methylene]- 6-fluoro-2-indolinone 10.23 3-Z-[1anilino-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2- indolinone 10.24 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-carboxymethylphenyl)- methylene]-6-fluoro-2-indolinone 10.25 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)- 1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.26 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1- (4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.27 3-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl)anilino)-1-(4- carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.28 3-Z-[1-(4-methylsulphonylanilino)-1-(4-carboxymethylphenyl)- methylene]-6-fluoro-2-indolinone 10.29 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-carboxymethylphenyl)- methylene]-6-fluoro-2-indolinone 10.30 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N- methylsulphonylamino)anilino)-1-(4-carboxymethylphenyl)methylene]- 6-fluoro-2-indolinone 10.31 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1- (4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.32 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)- 1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.33 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro- 2-indolinone 10.34 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.35 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.36 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1- (3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.37 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.38 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1- (4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.39 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.40 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1- (4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.41 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.42 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.43 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)- 1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.44 3-Z-[1-(4-(N-(4-dimethylamino-butylcarbonyl)-N-methylamino)anilino)- 1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.45 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.46 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1- (4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.47 3-Z-[1anilino-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2- indolinone 10.48 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.49 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.50 3-Z[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]- 6-fluoro-2-indolinone 10.51 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-carboxymethylphenyl)- methylene]-6-fluoro-2-indolinone 10.52 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-carboxymethylphenyl)- methylene]-6-fluoro-2-indolinone 10.53 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.54 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.55 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.56 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.57 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.58 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1- (3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.59 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.60 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.61 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.62 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1- (4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.63 3-Z-[1anilino-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2- indolinone 10.64 3-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]- 6-fluoro-2-indolinone 10.65 3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.66 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxy-phenyl)- methylene]-6-fluoro-2-indolinone 10.67 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethoxy- phenyl)phenyl)methylene]-6-fluoro-2-indolinone 10.68 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 10.69 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 10.70 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)- methylene]-6-bromo-2-indolinone 10.71 3-Z-[1-(3-dimethylaminomethylanilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.72 3-Z-[1-(3-dimethylaminomethylanilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.73 3-Z-[1-(3-dimethylaminomethylanilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 11.0 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carbamoyl- ethyl)phenyl)methylene]-6-chloro-2-indolinone 11.1 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methylcarbamoyl- ethyl)phenyl)methylene]-6-chloro-2-indolinone 11.2 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-methylcarbamoyl- ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.3 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3- dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.4 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carbamoyl- ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.5 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methylcarbamoyl- ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.6 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-dimethylcarbamoyl- ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.7 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carbamoylmethylphenyl)- methylene]-6-fluoro-2-indolinone 11.8 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3- methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.9 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carbamoylmethylphenyl)- methylene]-6-fluoro-2-indolinone 11.10 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-dimethylcarbamoyl- ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.11 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-(4-methylpiperazin-1-yl- carbonyl)ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.12 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-carbamoylmethylphenyl)methylene]-6-fluoro- 2-indolinone 11.13 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(4-carbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.14 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4- dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.15 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4- methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.16 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(4-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.17 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(4-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.18 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-methylcarbamoylmethylphenyl)methylene]-6- fluoro-2-indolinone 11.19 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2-methylcarbamoyl- ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.20 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-(2-methylcarbamoyl- ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.21 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)- 1-(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.22 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2- methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.23 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-methylcarbamoyl- ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.24 3-Z-[1-(4-methylsulphonylanilino)-1-(4-(2-methylcarbamoyl- ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.25 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2- methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.26 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3- methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.27 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-methylcarbamoylmethylphenyl)methylene]-6- fluoro-2-indolinone 12.0 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-acetylaminomethylphenyl)- methylene]-6-chloro-2-indolinone 12.1 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-acetylaminomethylphenyl)methylene)-6- chloro-2-indolinone 12.2 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-benzoylaminophenyl)- methylene]-6-chloro-2-indolinone 12.3 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-benzoylaminomethylphenyl)methylene]-6- chloro-2-indolinone 12.4 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-acetylaminomethylphenyl)- methylene]-6-fluoro-2-indolinone 12.5 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3- propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.6 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3- benzoylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.7 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3- phenylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.8 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.9 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- benzoylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.10 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- propionylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.11 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- phenylacetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.12 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-acetylaminomethylphenyl)- methylene]-6-fluoro-2-indolinone 12.13 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4- propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.14 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4- phenylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.15 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-acetylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 12.16 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-propionylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 12.17 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(4-phenylacetylaminomethylphenyl)- methylene]-6-fluoro-2-indolinone 12.18 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-cyclopropylcarbonylaminomethylphenyl)- methylene]-6-fluoro-2-indolinone 12.19 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-cyclobutylcarbonylaminomethylphenyl)- methylene]-6-fluoro-2-indolinone 12.20 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-(pyridin-2-yl- carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.21 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-cyclohexylcarbonylaminomethylphenyl)- methylene]-6-fluoro-2-indolinone 12.22 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-(pyridin-3-yl- carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.23 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-isobutyrylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 12.24 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-(3-methylbutyrylaminomethylphenyl)- methylene]-6-fluoro-2-indolinone 12.25 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3- cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2- indolinone 12.26 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-methoxyacetylaminomethylphenyl)- methylene]-6-fluoro-2-indolinone 12.27 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-(2-methoxybenzoyl- aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.28 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-tert-butylacetylaminomethylphenyl)- methylene]-6-fluoro-2-indolinone 12.29 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-(2-thiophen- carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.30 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-pivaloylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 12.31 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-(2-furoylaminomethyl)phenyl)methylene]-6- fluoro-2-indolinone 12.32 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 12.33 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-propionylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 12.34 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-benzoylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 12.35 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-phenylacetylaminomethylphenyl)- methylene]-6-fluoro-2-indolinone 12.36 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3- cyclopropylcarbonylaminomethylphenyl)methylene]-6-fluoro-2- indolinone 12.37 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3- cyclobutylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.38 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(pyridin-2-yl- carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.39 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3- cyclohexylcarbonylaminomethylphenyl)methylene]-6-fluoro-2- indolinone 12.40 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(pyridin-3-yl- carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.41 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3- isobutyrylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.42 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(3-methylbutyryl- aminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.43 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3- cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2- indolinone 12.44 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3- methoxyacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.45 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxybenzoyl- aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.46 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-tert- butylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.47 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- thiophenecarbonylaminomethyl)phenyl)methylene-6-fluoro-2- indolinone 12.48 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3- pivaloylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.49 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- furoylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.50 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(pyridin-4-yl- carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 13.0 3-Z-[1-(4-trimethylammoniummethylanilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone iodide 13.1 3-Z-[1-(4-trimethylammoniummethylanilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone iodide 14.0 3-Z-[1-(4-guanidinomethylanilino)-1-(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 14.1 3-Z-[1-(4-guanidinomethylanilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone Abbreviations used:

-   HOBt=1-hydroxy-1H-benzotriazole -   TBTU=O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium     tetrafluoroborate     Preparation of the Starting Materials:

EXAMPLE I

Dimethyl 2-(4-fluoro-2-nitrophenyl)malonate

With ice-cooling, 185 g of potassium tert-butoxide are added to a solution of 188 ml of dimethyl malonate in 970 ml of N-methylpyrrolidone, and the mixture is stirred for 2 hours. Over a period of 30 minutes, 150 ml of 2,5-difluoronitrobenzene are added dropwise to the resulting slurry, and the mixture is then stirred at 85° C. for 6 hours. The mixture is poured into 4 liters of ice-water and 250 ml of concentrated hydrochloric acid and extracted with 2 liters of ethyl acatate. The organic phase is dried with sodium sulphate and concentrated. The oily residue is triturated twice with water and then taken up in 600 ml of ethyl acetate. The solution is dried with sodium sulphate and concentrated to dryness. The resulting crude product is recrystallized from 600 ml of ethyl acetate/hexane=2:8 and dried.

Yield: 222 g (59% of theory)

R_(f) value: 0.40 (silica gel, cyclohexane/ethyl acetate=5:1)

C₁₁H₁₀FNO₆

Mass spectrum: m/z=270 [M−H]⁻

The following compounds are prepared analogously to Example I:

(I.1) Diethyl 2-(4-bromo-2-nitrophenyl)malonate from 2,5-dibromonitrobenzene and diethyl malonate

R_(f) value: 0.40 (silica gel, petroleum ether/ethyl acetate=5:1)

C₁₃H₁₄BrNO₆

Mass spectrum: m/z=359/361 [M]⁺

(I.2) Dimethyl 2-(4-cyano-2-nitrophenyl)malonate from 4-chloro-3-nitrobenzonitrile and dimethyl malonate

R_(f) value: 0.50 (silica gel, methylene chloride/methanol=50:1)

C₁₂H₁₀N₂O₆

Mass spectrum: m/z=277 [M−H]⁻

EXAMPLE II

Methyl 4-cyano-2-nitrophenylacetate

14.2 g of dimethyl 2-(4-cyano-2-nitrophenyl)malonate (starting material 1.2) are dissolved in 200 ml of dimethyl sulphoxide, and 4.5 g of lithium chloride and 1.0 ml of water are added. The solution is stirred at 100° C. for 3.5 hours, 300 ml of ice-water are then added and the mixture is allowed to stand for 12 hours. The resulting precipitate is filtered off with suction, taken up in methylene chloride and washed with water. The organic phase is dried over sodium sulphate, concentrated using a rotary evaporator and dried.

Yield: 7.7 g (68% of theory)

R_(f) value: 0.40 (silica gel, methylene chloride/methanol)=50:1

C₁₀H₈N₂O₄

Mass spectrum: m/z=219 [M−H]⁻

EXAMPLE III

4-Fluoro-2-nitrophenylacetic acid

At 100° C., 50.0 g of dimethyl 2-(4-fluoro-2-nitrophenyl)malonate (starting material 1) are stirred in 400 ml of 6 molar hydrochloric acid for 20 hours, 400 ml of water are then added and the mixture is cooled to 0° C. The resulting precipitate is filtered off with suction, washed with water and 100 ml of petroleum ether and dried.

Yield: 34.5 g (94% of theory)

R_(f) value: 0.30 (silica gel, cyclohexane/ethyl acetate)=5:2

C₈H₆FNO₄

Mass spectrum: m/z=154 [M-COO—H]⁻

EXAMPLE IV

6-Fluoro-2-indolinone

With addition of 20 g of palladium on activated carbon (10%), 119 g of 4-fluoro-2-nitrophenylacetic acid (starting material III) are hydrogenated in 600 ml of acetic acid under a hydrogen pressure of 50 psi. The catalyst is filtered off with suction and the solvent is distilled off. The crude product is triturated with 500 ml of petroleum ether, filtered off with suction, washed with water and dried.

Yield: 82.5 g (91% of theory)

R_(f) value: 0.30 (silica gel, petroleum ether/ethyl acetate 1:1)

C₈H₆FNO

Mass spectrum: m/z=150 [M−H]⁻

The following compounds are prepared analogously to Example IV:

(IV.1) 6-Bromo-2-indolinone

from diethyl 2-(4-bromo-2-nitrophenyl)malonate (starting material I.1) using Raney nickel as hydrogenation catalyst

R_(f) value: 0.45 (silica gel, petroleum ether/ethyl acetate=1:1)

C₈H₆BrNO

Mass spectrum: m/z=210/212 [M−H]⁻

(IV.2) 6-Cyano-2-indolinone

from methyl 4-cyano-2-nitrophenylacetate (starting material II) using palladium/calcium carbonate as hydrogenation catalyst

R_(f) value: 0.45 (silica gel, methylene chloride/methanol=9:1)

C₉H₆N₂O

Mass spectrum: m/z=157 [M−H]⁻

EXAMPLE V

1-acetyl-6-fluoro-2-indolinone

At 130° C., 82.5 g of 6-fluoro-2-indolinone (starting material IV) are stirred in 180 ml acetic anhydride for 3 hours. After cooling to room temperature, the precipitate is filtered off with suction, washed with 100 ml of petroleum ether and dried.

Yield: 64.8 g (61% of theory)

R_(f) value: 0.75 (silica gel, petroleum ether/ethyl acetate=1:1)

C₁₀H₈FNO₂

Mass spectrum: m/z=192 [M−H]⁻

The following compounds are prepared analogously to Example V:

(V.1) 1-acetyl-6-chloro-2-indolinone

from 6-chloro-2-indolinone and acetic anhydride

R_(f) value: 0.55 (silica gel, petroleum ether/ethyl acetate=2:3)

C₁₁H₁₀ClNO₆

Mass spectrum: m/z=208/210 [M−H]⁻

(V.2)1-acetyl-6-bromo-2-indolinone

from 6-bromo-2-indolinone (starting material IV.1) and acetic anhydride

R_(f) value: 0.60 (silica gel, petroleum ether/ethyl acetate=2:1)

C₁₀H₈BrNO₂

Mass spectrum: m/z=253/255 [M]⁺

(V.3)1-acetyl-6-cyano-2-indolinone

from 6-cyano-2-indolinone (starting material IV.2) and acetic anhydride

R_(f) value: 0.60 (silica gel, methylene chloride/methanol=50:1)

C₁₁H₈N₂O₂

Mass spectrum: m/z=199 [M−H]⁻

EXAMPLE VI

1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone

10.5 g of 1-acetyl-6-chloro-2-indolinone (starting material V.1), 13.6 g of 3-iodobenzoic acid and 17.7 g of TBTU are initially charged in 100 ml of dimethylformamide, 35 ml of triethylamine are added and the mixture is stirred at room temperature for 12 hours. After this time, the solvent is removed under reduced pressure, water is added to the residue and the residue is filtered off with suction, washed with a little water, methanol and ether and dried at 100° C. under reduced pressure.

Yield: 12.9 g (59% of theory)

R_(f) value: 0.80 (silica gel, methylene chloride/methanol=9:1)

C₁₇H₁₁ClINO₃

Mass spectrum: m/z=438/440 [M−H]⁻

The following compounds are prepared analogously to Example VI:

(VI.1) 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and methyl

(4-carboxyphenyl)acetate (preparation according to Tetrahedron 1997, 53, 7335-7340)

(VI.2)1-acetyl-3-[1-hydroxy-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-chlorobenzoic acid

(VI.3) 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone

from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 3,4-dimethoxybenzoic acid

(VI.4) 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)methylene]-6-cyano-2-indolinone

from 1-acetyl-6-cyano-2-indolinone (starting material V.3) and 3,4-dimethoxybenzoic acid

(VI.5) 1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-fluorobenzoic acid

(VI.6) 1-acetyl-3-[1-hydroxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-acetylaminoethyl)-benzoic acid (preparation according to J. Am. Chem. Soc. 1943, 65, 2377)

(VI.7)1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and methyl (3-carboxyphenyl)acetate (preparation analogously to Tetrahedron 1997, 53, 7335-7340)

(VI.8)1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonylaminomethyl)phenyl)-methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(N-tert-butoxycarbonyl-aminomethyl)benzoic acid (preparation according to Tetrahedron 1997, 53, 7335-7340)

(VI.9)1-acetyl-3-[1-hydroxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and (3-carboxyphenyl)-acetonitrile (preparation according to J. Prakt. Chem. 1998, 340, 367-374)

(VI.10) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonylaminomethyl)phenyl)-methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(N-tert-butoxycarbonyl-aminomethyl)benzoic acid (preparation according to Bioorg. Med. Chem. Lett 2000, 10, 553-557)

(VI.11) 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-iodobenzoic acid

(VI.12) 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-iodobenzoic acid

(VI.13) 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-iodobenzoic acid

(VI.14) 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340)

(VI.15) 1-acetyl-3-[1-hydroxy-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2-methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340)

(VI.16) 1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(N-tert-butoxycarbonyl-2-aminoethyl)benzoic acid (preparation analogously to Bioorg. Med. Chem. Lett 2000, 10, 553-557)

(VI.17) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(N-tert-butoxycarbonyl-2-aminoethyl)benzoic acid (preparation analogously to Bioorg. Med. Chem. Lett 2000, 10, 553-557)

(VI.18) 1-acetyl-3-[1-hydroxy-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone

from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-cyanobenzoic acid

(VI.19) 1-acetyl-3-[1-hydroxy-1-(3-acetylaminomethylphenyl)methylene)-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-acetylaminomethyl-benzoic acid (prepared according to J. Med. Chem. 1997, 40, 4030-4052)

(VI.20) 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2-ethoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340)

(VI.21) 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone

from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-(2-methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340)

(VI.22) 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-ethoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340)

(VI.23) 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyloxy-phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-methoxycarbonylmethyloxybenzoic acid (preparation see Tetrahedron Letters 1998, 39, 8563-8566)

(VI.24) 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethyloxyphenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-methoxycarbonylmethyloxybenzoic acid (preparation analogously to Tetrahedron Letters 1998, 39, 8563-8566)

(VI.25) 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2-ethoxycarbonylethyloxy)benzoic acid (preparation see PCT Int. Appl. WO9620173, 60)

(VI.26) 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-ethoxycarbonylethyloxy)benzoic acid (preparation see PCT Int. Appl. WO9620173, 58)

(VI.27) 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone

from 1-acetyl-6-bromo-2-indolinone (starting material V.2) and 4-(2-methoxycarbonylethyl)-benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340)

EXAMPLE VII

1-acetyl-3-[1-methoxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone

A little at a time, 2.36 g of trimethyloxonium tetrafluoroborate are added to a solution of 3.52 g of 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone (starting material VI) and 2.72 ml of ethyldiisopropylamine in 80 ml of dichloromethane, and the mixture is stirred at room temperature for one hour. Another 1.4 ml of ethyldiisopropylamine and 1.2 g of trimethyloxonium tetrafluoroborate are added, and the mixture is stirred at room temperature for another two hours. The mixture is then extracted with water and the organic phase is dried over magnesium sulphate and evaporated to dryness. The residue is recrystallized from ether and dried at 80° C. under reduced pressure.

Yield: 2.40 g (66% of theory)

R_(f) value: 0.60 (silica gel, petroleum ether/dichloromethane/ethyl acetate=5:4:1)

C₁₈H₁₃ClINO₃

Mass spectrum: m/z=438/440 [M−H]⁻

m.p. 185-187° C.

The following compounds are prepared analogously to Example VII:

(VII.1)1-acetyl-3-[1-methoxy-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone (starting material VI.1)

(VII.2)1-acetyl-3-[1-methoxy-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone (starting material VI.2)

(VII.3)1-acetyl-3-[1-methoxy-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone (starting material VI.3)

(VII.4) 1-acetyl-3-[1-methoxy-1-(3,4-dimethoxyphenyl)methylene]-6-cyano-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)-methylene]-6-cyano-2-indolinone (starting material VI.4)

(VII.5)1-acetyl-3-[1-methoxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone (starting material VI.5)

(VII.6) 1-acetyl-3-[1-methoxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.6)

(VII.7)1-acetyl-3-[1-methoxy-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone (starting material VI.7)

(VII.8)1-acetyl-3-[1-methoxy-1-(3-(N-tert-butoxycarbonylaminomethyl)phenyl)-methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.8)

(VII.9)1-acetyl-3-[1-methoxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(3-cyanomethyl phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.9)

(VII.10) 1-acetyl-3-[1-methoxy-1-(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.10)

(VII.11) 1-acetyl-3-[1-methoxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone (starting material VI.11)

(VII.12) 1-acetyl-3-[1-methoxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone (starting material VI.12)

(VII.13) 1-acetyl-3-[1-methoxy-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone (starting material VI.13)

(VII.14) 1-acetyl-3-[1-methoxy-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.14)

(VII.15) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.15)

(VII.16) 1-acetyl-3-[1-methoxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.17)

(VII.17) 1-acetyl-3-[1-methoxy-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.16)

(VII.18) 1-acetyl-3-[1-methoxy-1-(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone (starting material VI.19)

(VII.19) 1-acetyl-3-[1-methoxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.20)

(VII.20) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone (starting material VI.21)

(VII.21) 1-acetyl-3-[f-methoxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.22)

(VII.22) 1-acetyl-3-[1-methoxy-1-(4-methoxycarbonylmethyloxyphenyl)-methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethyloxyphenyl)methylene]-6-fluoro-2-indolinone (starting material VI.23)

(VII.23) 1-acetyl-3-[1-methoxy-1-(3-methoxycarbonylmethyloxyphenyl)-methylene]-6-fluoro-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyloxyphenyl)methylene]-6-fluoro-2-indolinone (starting material VI.24)

(VII.24) 1-acetyl-3-[1-methoxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.25)

(VII.25) 1-acetyl-3-[1-methoxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.26)

(VII.26) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone

from 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone (starting material VI.27)

EXAMPLE VIII

1-Acetyl-3-[1-chloro-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone

A suspension of 7.0 g of 1-acetyl-3-[1-hydroxy-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone (starting material VI.18) and 6.39 g of phosphorus pentachloride in 150 ml of dioxane is stirred at 100° C. for 6 hours. After addition of a further 1.0 g of phosphorus pentachloride, the mixture is stirred at 110° C. for another 4 hours. The solvent is then distilled off and the residue is washed with ethyl acetate.

Yield: 4.5 g (61% of theory)

R_(f) value: 0.70 (silica gel, methylene chloride/methanol 50:1)

C₁₈H₁₀Cl₂N₂O₂

EXAMPLE IX

The syntheses of the following compounds have already been described in the international application WO 01/27081:

(IX.1) 4-(diethylaminomethyl)aniline

(IX.2) N-(2-dimethylaminoethyl)-N-methylsulphonyl-p-phenylenediamine

(IX.3) 3-(dimethylaminomethyl)aniline

(IX.4) 4-(dimethylaminomethyl)aniline

(IX.5) 4-(2-dimethylaminoethyl)aniline

(IX.6) 4-[N-(2-dimethylaminoethyl)-N-acetylamino]aniline

(IX.7) 4-[N-(3-dimethylaminopropyl)-N-acetylamino]aniline

(IX.8) 4-[(N-dimethylaminocarbonylmethyl-N-methylsulphonyl)amino]aniline

(IX.9) N-(4-aminophenyl)-N-methylmethanesulphonamide

(IX.10) N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine

(IX.11) N-[(2-dimethylaminoethyl)carbonyl]-N-methyl-p-phenylenediamine

(IX.12) 4-(N-tert-butoxycarbonylaminomethyl)aniline

(IX.13) 4-(N-ethyl-N-tert-butoxycarbonylaminomethyl)aniline

(IX.14) 4-[(4-methylpiperazin-1-yl)methyl]aniline

(IX.15) 4-(imidazol-1-ylmethyl)aniline

(IX.16) 4-(1-methylimidazol-2-yl)aniline

(IX.17) 4-[(N-(2-dimethylaminoethyl)-N-methylamino)methyl]aniline

(IX.18) 4-(N-methyl-N-tert-butoxycarbonylaminomethyl)aniline

(IX.19) N-[(4-methylpiperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylenediamine

(IX.20) 4-(4-tert-butoxycarbonylpiperazin-1-ylmethyl)aniline

(IX.21) 4-(thiomorpholin-4-ylmethyl)aniline

(IX.22) 4-(pyrrolidin-1-ylmethyl)aniline

(IX.23) 4-(morpholin-4-yl-methyl)aniline

(IX.24) 4-(N-benzyl-N-methylaminomethyl)aniline

(IX.25) 4-(N-ethyl-N-methylaminomethyl)aniline

(IX.26) 4-[N-(2-dimethylaminoethyl)-N-methylamino]aniline

(IX.27) 4-[(N-propyl-N-methylamino)methyl]aniline

The following compounds are prepared analogously to Example IX:

(IX.28) 4-[N-(2-(N-benzyl-N-methylamino)ethyl)-N-acetylamino]aniline

(IX.29) 4-amino-N-(2-dimethylaminoethyl)-N-methylbenzamide

(IX.30) 4-(4-methylpiperazin-1-ylcarbonyl)aniline

(IX.31) 4-(2-dimethylaminoethoxy)aniline

(IX.32) N-(4-dimethylaminobutylcarbonyl)-N-methyl-p-phenylenediamine

(IX.33) N-[(3-dimethylaminopropyl)carbonyl]-N-methyl-p-phenylenediamine

Preparation of the End Products:

EXAMPLE 1.0

3-Z-f 1-(4-(N-Methyl-N-methylsulphonylamino)anilino)-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone

0.9 g of 1-acetyl-3-(1-methoxy-1-(3-iodophenyl)methylene)-6-chloro-2-indolinone (starting material VII) and 0.5 g of N-methyl-N-methylsulphonyl-p-phenylenediamine (starting material IX.9) are dissolved in 10 ml of dimethylformamide and stirred at 120° C. for 3 hours. After cooling, 1.5 ml of piperidine are added and the mixture is stirred at room temperature for another hour. Water is added and the resulting precipitate is filtered off with suction, washed with a little water, methanol and ether and finally dried under reduced pressure at 100° C.

Yield: 0.9 g (74% of theory),

R_(f) value: 0.6 (silica gel, methylene chloride/methanol=9:1)

m.p. 292-294° C.

C₂₃H₁₉ClIN₃O₃S

Mass spectrum: m/z=578/580 [M−H]⁻

The following compounds of the formula I-1 are prepared analogously to Example 1.0: (I-1)

Ex- Starting Empirical Mass m.p. R_(f) ample R³ R^(4′) materials formula spectrum [° C.] value* 1.1

—CH₂—NMe₂ VII IX.4 C₂₄H₂₁CllN₃O 529/531 [M+H]⁺ 238-240 0.30(A) 1.2

—N(Me)—(CO)—CH₂—NMe₂ VII.2 IX.10 C₂₆H₂₄Cl₂N₄O₂ 495/497 [M+H]⁺ 277-279 0.20(B) 1.3

—N(COMe)—(CH₂)₂—NMe₂ VII.2 IX.6 C₂₇H₂₆Cl₂N₄O₂ 507/509 [M−H]⁻ 241-243 0.10(B) 1.4

VII.2 IX.19 C₂₉H₂₉Cl₂N₅O₂ 548/550 [M−H]⁻ 266-268 0.10(B) 1.5

—N(COMe)—(CH₂)₃—NMe₂ VII.2 IX.7 C₂₈H₂₈Cl₂N₄O₂ 521/523 [M−H]⁻ 241-242 0.10(B) 1.6

—CH₂—NMe₂ VII.2 IX.4 C₂₄H₂₁Cl₂N₃O 438/440 [M+H]⁺ 243-244 0.10(B) 1.7

—N(COMe)—(CH₂)₂—NMe₂ VII.3 IX.6 C₂₉H₃₁ClN₄O₄ 533/535 [M−H]⁻ 128-130 0.75(C) 1.8

VII.3 IX.19 C₃₁H₃₄ClN₅O₄ 574/576 [M−H]⁻ 208-210 0.65(C) 1.9

—N(SO₂Me)—(CH₂)₂—NMe₂ VII.3 IX.2 C₂₈H₃₁ClN₄O₅S 569/571 [M−H]⁻ 198-200 0.75(C) 1.10

—CH₂—NMe₂ VII.3 IX.4 C₂₆H₂₆ClN₃O₃ 462/464 [M−H]⁻ 239-240 0.70(C) 1.11

VII.3 IX.29 C₂₉H₃₁ClN₄O₄ 533/535 [M−H]⁻ 147-149 0.70(C) *Eluent mixtures: (A): silica gel, methylene chloride/methanol 9:1 (B): silica gel, methylene chloride/ethanol 10:1 (C): silica gel, methylene chloride/methanol 4:1

EXAMPLE 2.0

3-Z-[1-(4-(Dimethylaminomethyl)anilino)-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone

1.07 g of 1-acetyl-3-[1-chloro-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone (starting material VII) and 0.54 g of 4-(dimethylaminomethyl)aniline (starting material IX.4) are dissolved in 10 ml of dimethylformamide and stirred at 80° C. for 3 hours. After cooling, 1 ml of 6N aqueous sodium hydroxide is added, and the mixture is stirred at room temperature for 30 minutes. Water is added and the mixture is extracted three times with methylene chloride. The combined organic phases are washed twice with water, dried over sodium sulphate and concentrated using a rotary evaporator, and the product is recrystallized from diethyl ether.

Yield: 0.92 g (72% of theory),

R_(f) value: 0.1 (silica gel, methylene chloride/methanol=9:1)

C₂₅H₂₁ClN₄O

Mass spectrum: m/z=427/429 [M−H]⁻

EXAMPLE 3.0

3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone

3.5 g of 1-acetyl-3-(1-methoxy-1-(4-iodophenyl)methylene)-6-fluoro-2-indolinone (starting material VII.11) and 1.6 g of 4-(dimethylaminomethyl)aniline (starting material IX.4) are dissolved in 30 ml of dimethylformamide and stirred at 120° C. for 2 hours. After cooling, the solvent is removed under reduced pressure, the residue is taken up in 30 ml of methanol and 2 spatula tips of sodium methoxide are added. Once a yellow precipitate has formed, this is filtered off with suction from the solvent and the residue is washed with a little methanol and ether and finally dried under reduced pressure at 100° C.

Yield: 1.9 g (46% of theory),

R_(f) value: 0.3 (silica gel, methylene chloride/methanol=9:1)

m.p. 243-246° C.

C₂₄H₂₁FIN₃O

Mass spectrum: m/z=514 [M+H]⁺

The following compounds of the formula I-3a are prepared analogously to Example 3.0: (I-3a)

Ex- Starting Empirical Mass m.p. R_(f) ample R² R³ R^(4′) materials formula spectrum [° C.] value* 3.1 -F

—CH₂—NMe₂ VII.5 IX.4 C₂₄H₂₁F₂N₃O 404 [M−H]⁻ 225-227 0.20(A) 3.2 -F

—N(COMe)—(CH₂)₃—NMe₂ VII.5 IX.7 C₂₈H₂₈F₂N₄O₂ 491 [M+H]⁺ 160-163 0.20(A) 3.3 -F

VII.5 IX.19 C₂₉H₂₉F₂N₅O₂ 518 [M+H]⁺ 218-220 0.40(A) 3.4 -F

—CH₂—NMe₂ VII.6 IX.4 C₂₈H₂₉FN₄O₂ 471 [M−H]⁻ 106-110 0.25(A) 3.5 -F

—N(COMe)—(CH₂)₃—NMe₂ VII.6 IX.7 C₃₂H₃₆FN₅O₃ 558 [M+H]⁺ 194-196 0.25(A) 3.6 -F

VII.6 IX.19 C₃₃H₃₇FN₆O₃ 583 [M−H]⁻ 238-240 0.25(A) 3.7 -F

—CH₂—NMe₂ VII.1 IX.4 C₂₇H₂₆FN₃O₃ 460 [M+H]⁺ 173-176 0.30(A) 3.8 -F

—CH₂—NMe₂ VII.13 IX.4 C₂₄H₂₁FIN₃O 514 [M+H]⁺ 198-200 0.30(B) 3.9 -F

—CH₂—NMe₂ VII.7 IX.4 C₂₇H₂₆FN₃O₃ 458 [M−H]⁻ 195-198 0.25(A) 3.10 -F

—CH₂—NMe₂ VII.8 IX.4 C₃₀H₃₃FN₄O₃ 517 [M+H]⁺ 230-240 0.30(A) 3.11 -F

—N(SO₂Me)—(CH₂)₂—NMe₂ VII.1 IX.2 C₂₉H₃₁FN₄O₅S 567 [M+H]⁺ 188-189 0.40(A) 3.12 -F

VII.1 IX.19 C₃₂H₃₄FN₅O₄ 572 [M+H]⁺ 200-203 0.35(C) 3.13 -F

—CH₂—NMe₂ VII.9 IX.4 C₂₆H₂₃FN₄O 427 [M+H]⁺ 130-135 0.25(A) 3.14 -F

VII.10 IX.19 C₃₅H₄₁FN₆O₄ 629 [M+H]⁺ 215-220 0.35(A) 3.15 -F

—CH₂—NMe₂ VII.10 IX.4 C₃₀H₃₃FN₄O₃ 517 [M+H]⁺ 186-190 0.35(A) 3.16 -F

—CH₂—NMe₂ VII.17 IX.4 C₃₁H₃₅FN₄O₃ 531 [M+H]⁺ n.d 0.40(A) 3.17 -F

—NMe—(COMe) VII.15 — C₂₈H₂₆FN₃O₄ 488 [M+H]⁺ 166-170 0.40(A) 3.18 -F

VII.15 IX.19 C₃₃H₃₆FN₅O₄ 586 [M+H]⁺ 176-180 0.30(A) 3.19 -F

—N(SO₂Me)—(CH₂)₂—NMe₂ VII.15 IX.2 C₃₀H₃₃FN₄O₅S 581 [M+H]⁺ 195-198 0.45(A) 3.20 -F

—N(COMe)—(CH₂)₃—NMe₂ VII.15 IX.7 C₃₂H₃₅FN₄O₄ 559 [M+H]⁺ 100-104 0.50(A) 3.21 -F

VII.15 IX.18 C₃₂H₃₄FN₃O₅ 558 [M−H]⁻ 132-137 0.80(D) 3.22 -F

VII.15 IX.30 C₃₁H₃₁FN₄O₄ 543 [M+H]⁺ 234-236 0.60(A) 3.23 -F

VII.15 IX.16 C₂₉H₂₅FN₄O₃ 497 [M+H]⁺ 110-115 0.40(A) 3.24 -F

—SO₂Me VII.15 — C₂₆H₂₃FN₂O₅S 495 [M+H]⁺ 130-137 0.60(A) 3.25 -F

VII.7 IX.19 C₃₂H₃₄FN₅O₄ 572 [M+H]⁺ 189 0.60(B) 3.26 -F

—N(SO₂Me)—(CH₂)₂—NMe₂ VII.7 IX.2 C₂₉H₃₁FN₄O₅S 567 [M+H]⁺ n.d 0.60(B) 3.27 -F

VII.7 IX.30 C₃₀H₂₉FN₄O₄ 529 [M+H]⁺ 201-203 0.60(B) 3.28 -F

—N(Me)—(CO)—CH₂—NMe₂ VII.7 IX.10 C₂₉H₂₉FN₄O₄ 517 [M+H]⁺ 126 0.60(B) 3.29 -F

—N(COMe)—(CH₂)₂—NMe₂ VII.7 IX.6 C₃₀H₃₁FN₄O₄ 531 [M+H]⁺ 179 0.50(B) 3.30 -F

—N(COMe)—(CH₂)₃—NMe₂ VII.7 IX.7 C₃₁H₃₃FN₄O₄ 545 [M+H]⁺ 123 0.20(B) 3.31 -F

—N(Me)—(CO)—(CH₂)₄—NMe₂ VII.7 IX.32 C₃₂H₃₅FN₄O₄ 559 [M+H]⁺ 201 0.20(B) 3.32 -F

-H VII.1 — C₂₄H₁₉FN₂O₃ 403 [M+H]⁺ 198-206 0.80(A) 3.33 -F

VII.1 IX.16 C₂₈H₂₃FN₄O₃ 483 [M+H]⁺ 223-226 0.75(A) 3.34 -F

VII.1 IX.30 C₃₀H₂₉FN₄O₄ 529 [M+H]⁺ 215-220 0.30(A) 3.35 -F

—N(SO₂Me)—(CH₂)—(CO)—NMe₂ VII.1 IX.8 C₂₉H₂₉FN₄O₆S 581 [M+H]⁺ 227-230 0.65(A) 3.36 -F

—N(Me)—(CO)—CH₂—NMe₂ VII.1 IX.10 C₂₉H₂₉FN₄O₄ 517 [M+H]⁺ 128-130 0.45(A) 3.37 -F

—N(COMe)—CH₃ VII.1 — C₂₇H₂₄FN₃O₄ 474 [M+H]⁺ 218-223 0.40(A) 3.38 -F

—N(Me)—(CO)—(CH₂)₂—NMe₂ VII.1 IX.11 C₃₀H₃₁FN₄O₄ 531 [M+H]⁺ 192-194 0.40(A) 3.39 -F

—SO₂Me VII.1 — C₂₅H₂₁FN₂O₅S 481 [M+H]⁺ 205-214 0.65(A) 3.40 -F

—N(Me)—(CO)—(CH₂)₃—NMe₂ VII.1 IX.33 C₃₁H₃₃FN₄O₄ 545 [M+H]⁺ 190-193 0.15(A) 3.41 -F

—N(COMe)—(CH₂)₃—NMe₂ VII.1 IX.7 C₃₁H₃₃FN₄O₄ 545 [M+H]⁺ 184-188 0.50(A) 3.42 -F

-H VII.7 — C₂₄H₁₉FN₂O₃ 403 [M+H]⁺ 114 0.70(B) 3.43 -F

—SO₂Me VII.7 — C₂₅H₂₁FN₂O₅S 481 [M+H]⁺ 129 0.60(B) 3.44 -F

VII.7 IX.16 C₂₈H₂₃FN₄O₃ 483 [M+H]⁺ 125 0.60(B) 3.45 -F

—N(SO₂Me)—(CH₂)—(CO)—NMe₂ VII.7 IX.8 C₂₉H₂₉FN₄O₆S 581 [M+H]⁺ 163 0.60(B) 3.46 -F

—N(Me)—(CO)—(CH₂)₃—NMe₂ VII.7 IX.33 C₃₁H₃₃FN₄O₄ 545 [M+H]⁺ 101 0.10(B) 3.47 -F

—N(Me)—(CO)—(CH₂)₂—NMe₂ VII.7 IX.11 C₃₀H₃₁FN₄O₄ 531 [M+H]⁺ 161 0.20(B) 3.48 -F

VII.14 IX.19 C₃₀H₃₁FN₄O₄ 586 [M+H]⁺ 181-183 0.20(B) 3.49 -F

—N(SO₂Me)—(CH₂)₂—NMe₂ VII.14 IX.2 C₃₀H₃₃FN₄O₅S 581 [M+H]⁺ 158-160 0.35(B) 3.50 -F

—N(Me)—(CO)—CH₂—NMe₂ VII.14 IX.10 C₃₀H₃₁FN₄O₄ 531 [M+H]⁺ n.d. 0.40(B) 3.51 -F

—N(COMe)—(CH₂)₃—NMe₂ VII.14 IX.7 C₃₂H₃₅FN₄O₄ 559 [M+H]⁺ n.d. 0.50(E) 3.52 -F

VII.8 IX.19 C₃₅H₄₁FN₆O₄ 629 [M+H]⁺ n.d. 0.35(A) 3.53 -F

—NMe—(CO)—CH₃ VII.26 — C₂₇H₂₅FN₄O₃ 473 [M+H]⁺ 122-126 0.50(F) 3.54 -F

—N(COMe)—(CH₂)₃—NMe₂ VII.26 IX.7 C₃₁H₃₄FN₅O₃ 544 [M+H]⁺ 80-83 0.25(A) 3.55 -F

—N(SO₂Me)—(CH₂)₂—NMe₂ VII.18 IX.2 C₂₉H₃₂FN₅O₄S 566 [M+H]⁺ 190-195 0.30(A) 3.56 -F

—N(Me)—(CO)—CH₂—NMe₂ VII.18 IX.10 C₂₉H₃₀FN₅O₃ 516 [M+H]⁺ 238-241 0.30(G) 3.57 -F

—(CH₂)₂—NMe₂ VII.15 IX.5 C₂₉H₃₀FN₃O₃ 488 [M+H]⁺ 205-208 0.55(G) 3.58 -F

—N(Me)—(CO)—(CH₂)₂—NMe₂ VII.15 IX.11 C₃₁H₃₁FN₄O₄ 543 [M−H]⁻ 196-202 0.20(A) 3.59 -F

—N(Me)—(CO)—CH₂—NMe₂ VII.15 IX.10 C₃₀H₃₁FN₄O₄ 531 [M+H]⁺ 177-182 0.30(A) 3.60 -F

—(CH₂)₂—NMe₂ VII.19 IX.5 C₃₀H₃₂FN₃O₃ 500 [M−H]⁻ 100-105 0.35(B) 3.61 -F

—N(COMe)—(CH₂)₂—NMe₂ VII.15 IX.6 C₃₁H₃₃FN₄O₄ 545 [M+H]⁺ 167-169 0.40(A) 3.62 -F

—N(Me)—(CO)—(CH₂)₃—NMe₂ VII.19 IX.33 C₃₃H₃₇FN₄O₄ 571 [M−H]⁻ n.d. 0.35(A) 3.63 -F

—N(Me)—(CO)—(CH₂)₄—NMe₂ VII.19 IX.32 C₃₄H₃₉FN₄O₄ 585 [M−H]⁻ n.d. 0.40(A) 3.64 -F

VII.19 IX.16 C₃₀H₂₇FN₄O₃ 511 [M+H]⁺  95-105 0.25(B) 3.65 -F

—N(Me)—(CO)—(CH₂)₄—NMe₂ VII.15 IX.32 C₃₃H₃₇FN₄O₄ 573 [M+H]⁺ 173-175 0.20(A) 3.66 -F

-H VII.15 — C₂₅H₂₁FN₂O₃ 417 [M+H]⁺ 168-174 0.65(A) 3.67 -F

VII.15 IX.22 C₃₀H₃₀FN₃O₃ 500 [M+H]⁺ 168-173 0.40(B) 3.68 -F

—CH₂—NEt₂ VII.15 IX.1 C₃₀H₃₂FN₃O₃ 502 [M+H]⁺ n.d. 0.45(B) 3.69 -F

VII.15 IX.12 C₃₁H₃₂FN₃O₅ 544 [M−H]⁻ n.d. 0.30(G) 3.70 -F

—(CH₂)₂—NMe₂ VII.7 IX.5 C₂₈H₂₈FN₃O₃ 472 [M−H]⁻ 165-170 0.25(B) 3.71 -F

—(CH₂)₂—NMe₂ VII.1 IX.5 C₂₈H₂₈FN₃O₃ 472 [M−H]⁻ 193-197 0.25(B) 3.72 -F

—CH₂—NMe₂ VII.19 IX.4 C₂₉H₃₀FN₃O₃ 488 [M+H]⁺ 48-52 0.45(B) 3.73 -Cl

—(CH₂)₂—NMe₂ VII.20 IX.5 C₂₉H₃₀ClN₃O₃ 504/506 [M+H]⁺ 156-160 0.30(H) 3.74 -Cl

VII.20 IX.16 C₂₉H₂₅ClN₄O₃ 513/515 [M+H]⁺ 110 0.40(H) 3.75 -Cl

—CH₂—NMe₂ VII.20 IX.4 C₂₈H₂₈ClN₃O₃ 490/492 [M+H]⁺ 173-175 0.70(I) 3.76 -F

—CH₂—NMe₂ VII.21 IX.4 C₂₉H₃₀FN₃O₃ 488 [M+H]⁺ 158-161 0.35(B) 3.77 -F

VII.14 IX.14 C₃₁H₃₃FN₄O₃ 529 [M+H]⁺ 147-105 0.50(I) 3.78 -F

VII.14 IX.15 C₂₉H₂₅FN₄O₃ 497 [M+H]⁺ 182-185 0.60(K) 3.79 -F

VII.15 IX.14 C₃₁H₃₃FN₄O₃ 529 [M+H]⁺ 184 0.35(B) 3.80 -F

VII.15 IX.15 C₂₉H₂₅FN₄O₃ 497 [M+H]⁺ 233 0.45(B) 3.81 -F

—CH₂—NMe—(CH₂)₂—NMe₂ VII.15 IX.17 C₃₁H₃₅FN₄O₃ 531 [M+H]⁺ 120 0.40(B) 3.82 -F

—CH₂—NMe—(CH₂)₂—NMe₂ VII.19 IX.17 C₃₂H₃₇FN₄O₃ 545 [M+H]⁺ n.d. 0.40(K) 3.83 -Cl

VII.20 IX.22 C₃₀H₃₀ClN₃O₃ 516/518 [M+H]⁺ 195-197 0.30(H) 3.84 -F

-H VII.19 — C₂₆H₂₃FN₂O₃ 431 [M+H]⁺ 156-160 0.80(M) 3.85 -F

VII.19 IX.12 C₃₂H₃₄FN₃O₅ 560 [M+H]⁺ n.d. 0.50(L) 3.86 -F

VII.19 IX.18 C₃₃H₃₆FN₃O₅ 574 [M+H]⁺ n.d. 0.60(L) 3.87 -F

—CH₂—NMe₂ VII.22 IX.4 C₂₇H₂₆FN₃O₄ 476 [M+H]⁺ 129 0.25(B) 3.88 -F

—CH₂—NMe₂ VII.23 IX.4 C₂₇H₂₆FN₃O₄ 476 [M+H]⁺ 155 0.25(B) 3.89 -F

—CH₂—NMe₂ VII.24 IX.4 C₂₉H₃₀FN₃O₄ 504 [M+H]⁺ n.d. 0.20(B) 3.90 -Br

VII.26 IX.22 C₃₀H₃₀BrN₃O₃ 560/562 [M+H]⁺ 230-235 0.45(B) 3.91 -Br

—CH₂—NMe₂ VII.26 IX.4 C₂₈H₂₈BrN₃O₃ 534/536 [M+H]⁺ 178-180 0.35(B) 3.92 -Br

—CH₂—NEt₂ VII.26 IX.1 C₃₀H₃₂BrN₃O₃ 562/564 [M+H]⁺ 173-176 0.40(B) *Eluent mixtures: (A): silica gel, methylene chloride/methanol/ammonia 9:1:0.1 (B): silica gel, methylene chloride/methanol 9:1 (C): silica gel, methylene chloride/methanol/ammonia 8:1:0.1 (D): silica gel, methylene chloride/methanol/ammonia 10:1:0.1 (E): silica gel, methylene chloride/methanol/ammonia 5:1:0.01 (F): silica gel, ethyl acetate/methanol/ammonia = 9:1:0,1 (G): alumina, methylene chloride/methanol = 19:1 (H): silica gel, methylene chloride/methanol/ammonia 9:1:0.01 (I): silica gel, methylene chloride/methanol 5:1 (K): alumina, methylene chloride/ethanol = 20:1 (L): silica gel, petroleum ether/ethyl acetate 1:1 (M): silica gel, petroleum ether/ethyl acetate 1:2

The following compounds of the formula I-3b are prepared analogously to Example 3.0: (I-3b)

Ex- Starting Empirical Mass m.p. R_(f) ample R² R³ R^(4′) materials formula spectrum [° C.] value* 3.93 -F

—CH₂—NMe₂ VII.15 IX.3 C₂₈H₂₈FN₃O₃ 474 [M+H]⁺ 179-179 0.40(A) 3.94 -F

—CH₂—NMe₂ VII.19 IX.3 C₂₉H₃₀FN₃O₃ 486 [M−H]⁻ n.d. 0.45(B) 3.95 -Cl

—CH₂—NMe₂ VII.20 IX.3 C₂₈H₂₈ClN₃O₃ 490/492 [M+H]⁺ 163-165 0.40(A) *Eluent mixtures: (A): silica gel, methylene chloride/methanol 9:1 (B): silica gel, methylene chloride/methanol/ammonia 9:1:0.1

EXAMPLE 4.0

3-Z-[1-(4-(Dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-cyano-2-indolinone

130 mg of 1-acetyl-3-(1-methoxy-1-(3,4-dimethoxyphenyl)methylene)-6-cyano-2-indolinone (starting material VI1.4) and 58 mg of 4-(dimethylaminomethyl)aniline (starting material IX.4) are dissolved in 5 ml of dimethylformamide and stirred at 80° C. for 2 hours. After cooling, the solvent is removed under reduced pressure and the residue is purified on a silica gel column using the mobile phase methylene chloride/methanol 9:1.

Yield: 21 mg (12% of theory),

R_(f) value: 0.35 (silica gel, methylene chloride/methanol=9:1)

m.p. 265° C.

C₂₇H₂₆N₄O₃

EXAMPLE 5.0

3-Z-[1-(4-(N-Methyl-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-chloro-2-indolinone

580 mg of 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-iodophenyl)-methylene]-6-chloro-2-indolinone (starting material 1.0) and 140 ml of methyl acrylate are dissolved in 20 ml of acetonitrile and 11 ml of dimethylformamide, and 11 mg of palladium(II) acetate, 2 ml of triethylamine and 30 mg of tri-ortho-tolylphosphine are added. Under nitrogen as protective gas, the solution is stirred at 90° C. for 10 hours. After cooling, the solution is filtered through Celite, the solvent is removed under reduced pressure and the residue is purified on a silica gel column using the mobile phase methylene chloride/methanol 20:1.

Yield: 450 mg (84% of theory),

R_(f) value: 0.30 (silica gel, toluene/ethyl acetate=1:1)

m.p. 228-232° C.

C₂₇H₂₄ClN₃O₅S

Mass spectrum: m/z=537/539 [M]⁺

The following compounds of the formula I-5 are prepared analogously to Example 5.0: (I-5)

Ex- Starting Empirical Mass m.p. R_(f)- ample R² R³ R^(4′) materials formula spectrum [° C.] value* 5.1 -Cl

—CH₂—NMe₂ 1.1 C₂₈H₂₆ClN₃O₃ 486/488 [M−H]⁻ 150-155 0.50(A) 5.2 -F

—CH₂—NMe₂ 3.0 C₂₇H₂₅FN₄O₂ 455 [M−H]⁻ 269-270 0.20(B) 5.3 -F

—CH₂—NMe₂ 3.0 C₂₈H₂₆FN₃O₃ 470 [M−H]⁻ 205-208 0.65(A) 5.4 -F

—CH₂—NMe₂ 1.1 C₂₈H₂₆FN₃O₃ 472 [M+H]⁺ 138-140 0.45(A) *Eluent mixtures: (A): silica gel, methylene chloride/methanol 5:1 (B): silica gel, methylene chloride/methanol/ammonia 9:1:0.01

EXAMPLE 6.0

3-Z-[1-(4-Dimethylaminomethylanilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone

1.0 g of 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-chloro-2-indolinone (starting material 5.1) is dissolved in 100 ml of methanol, and 200 mg of 10 percent palladium/carbon as catalyst are added. The mixture is then hydrogenated at room temperature and a hydrogen pressure of 50 psi for 6 hours. After the reaction has ended, the catalyst is filtered off, the solvent is removed under reduced pressure and the residue is dried under reduced pressure at 100° C.

Yield: 900 mg (90% of theory),

R_(f) value: 0.40 (silica gel, methylene chloride/methanol=9:1)

m.p. 160° C.

C₂₈H₂₈ClN₃O₃

Mass spectrum: m/z=490/492 [M+H]⁺

The following compounds of the formula I-6 are prepared analogously to Example 6.0: (I-6)

Ex- Starting Empirical Mass m.p. R_(f) ample R² R³ R^(4′) materials formula spectrum [° C.] value* 6.1 -Cl

—N(Me)—SO₂Me 5.0 C₂₇H₂₆ClN₃O₅S 538/540 [M−H]⁻ 148-150 0.50(A) 6.2 -F

—CH₂—NMe₂ 5.2 C₂₇H₂₇FN₄O₂ 459 [M+H]⁺ 150 0.70(B) 6.3 -F

—CH₂—NMe₂ 5.3 C₂₈H₂₈FN₃O₃ 474 [M+H]⁺ 140 0.35(A) 6.4 -F

—CH₂—NMe₂ 5.4 C₂₈H₂₈FN₃O₃ 474 [M+H]⁺ 140-142 0.30(A) *Eluent mixtures: (A): silica gel, methylene chloride/methanol 9:1 (B): silica gel, methylene chloride/methanol/ammonia 5:1:0.01

EXAMPLE 7.0

3-Z-[1-(4-Dimethylaminomethylanilino)-1-(4-aminomethylphenyl)methylene]-6-chloro-2-indolinone

900 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone (starting material 2.0) are dissolved in 20 ml of methylene chloride and 30 ml of methanolic ammonia and, as catalyst, 200 mg of Raney nickel are added. The mixture is then hydrogenated at room temperature and a hydrogen pressure of 50 psi for 2 hours and 15 minutes. After the reaction has ended, the catalyst is filtered off, the solvent is removed under reduced pressure and the residue is washed with a little methanol and diethyl ether. To liberate the base, the residue is taken up in 1 N aqueous sodium hydroxide solution and extracted four times with methylene chloride/methanol 9:1. The combined organic phases are washed with water and dried over sodium sulphate. The product is washed with a little diethyl ether and dried under reduced pressure.

Yield: 680 mg (75% of theory),

R_(f) value: 0.60 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1)

m.p. 211-214° C.

C₂₅H₂₅ClN₄O

Mass spectrum: m/z=433/435 [M+H]⁺

EXAMPLE 8.0

3-Z-[1-(4-(N-((4-Methylpiperazin-1-yl)methylcarbonyl)-N-methylamino)anilino)-1-(4-aminomethylphenyl)methylene]-6-chloro-2-indolinone

1.39 g of 1-acetyl-3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-methylamino)anilino)-1-(4-cyanophenyl)methylene)-6-chloro-2-indolinone are dissolved in 20 ml of methylene chloride and 30 ml of methanolic ammonia and, as catalyst, 200 mg of Raney nickel are added. The mixture is then hydrogenated at room temperature at a hydrogen pressure of 50 psi for 2 hours. After the reaction has ended, the catalyst is filtered, the solvent is removed under reduced pressure and the residue is washed with a little methanol and diethyl ether. To liberate the base, the residue is taken up in 1 N aqueous sodium hydroxide solution and extracted four times with methylene chloride/methanol 9:1. The combined organic phases are washed with water and dried over sodium sulphate. The product is purified on a silica gel column using, as mobile phase, a gradient of methylene chloride and methylene chloride/methanol/ammonia 8:1:0.1. The product is washed with a little diethyl ether and dried under reduced pressure.

Yield: 700 mg (54% of theory),

R_(f) value: 0.15 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1)

m.p. 232-235° C.

C₃₀H₃₃ClN₆O₂

Mass spectrum: m/z=544/546 [M]⁺

EXAMPLE 9.0

3-Z-[1-(4-(Dimethylaminomethyl)anilino)-1-(3-aminomethylphenyl)methylene]-6-fluoro-2-indolinone

2.72 g of 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 3.10) are dissolved in 50 ml of methylene chloride, and 10 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 3 hours. After this time, most of the solvent is removed under reduced pressure and the residue is taken up in ethyl acetate and washed twice with 1 N aqueous sodium hydroxide solution. The organic phase is dried over sodium sulphate, the solvent is removed using a rotary evaporator and the residue is purified on a silica gel column using the mobile phase methylene chloride/methanol/ammonia 9:1:0.1. The product is washed with a little diethyl ether and dried under reduced pressure.

Yield: 1.77 g (81% of theory),

R_(f) value: 0.25 (silica gel, methylene chloride/methanol/ammonia 9:1:0.1)

m.p. 168-175° C.

C₂₅H₂₅FN₄O

Mass spectrum: m/z=415 [M−H]⁻

The following compounds of the formula I-9 are prepared analogously to Example 9.0: (I-9)

Ex- Starting Empirical Mass m.p. R_(f) ample R² R³ R^(4′) materials formula spectrum [° C.] value* 9.1 -F

—CH₂—NMe₂ 3.16 C₂₆H₂₇FN₄O 431 [M+H]⁺ 155-160 0.45(C) 9.2 -F

—CH₂—NMe₂ 3.15 C₂₅H₂₅FN₄O 417 [M+H]⁺ 203-207 0.25(A) 9.3 -F

3.14 C₃₀H₃₃FN₆O₂ 529 [M+H]⁺ 170-175 0.15(A) 9.4 -F

—CH₂—NHMe 10.11 C₂₆H₂₄FN₃O₃ 446 [M+H]⁺ 245-251 0.20(D) 9.5 -F

—CH₂—NHMe 11.22 C₂₆H₂₄FN₃O₃ 459 [M+H]⁺ 239-243 0.30(A) 9.6 -F

3.52 C₃₀H₃₃FN₆O₂ 529 [M+H]⁺ n.d. n.d. 9.7 -F

—CH₂—NH₂ 3.69 C₂₆H₂₄FN₃O₃ 444 [M−H]⁻ 158-163 0.25(A) 9.8 -F

—CH₂—NH₂ 3.85 C₂₇H₂₆FN₃O₃ 460 [M+H]⁺ 205-210 0.30(B) 9.9 -F

—CH₂—NHMe 3.86 C₂₈H₂₈FN₃O₃ 474 [M+H]⁺ 148-150 0.30(B) *Eluent mixtures: (A): silica gel, methylene chloride/methanol/ammonia 9:1:0.1 (B): silica gel, methylene chloride/methanol/ammonia 9:1:0.01 (C): silica gel, methylene chloride/methanol/ammonia 8:2:0.2 (D): Reversed phase RP8, methanol/sodium chloride solution(5%) = 3:2

EXAMPLE 10.0

3-Z-[1-(4-Dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone

900 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone (starting material 6.0) are dissolved in 10 ml of ethanol, and 5 ml of 1 N aqueous sodium hydroxide solution are added. The mixture is stirred at room temperature for 5 hours. After cooling, 5 ml of 1 N hydrochloric acid are added. The resulting precipitate is filtered off with suction and washed with water.

Yield: 830 mg (95% of theory),

R_(f) value: 0.50 (reversed phase RP8, methanol/sodium chloride solution (5%)=4:1)

m.p. 210-215° C.

C₂₇H₂₆ClN₃O₃

Mass spectrum: m/z=476/478 [M+H]⁺

The following compounds of the formula I-10a are prepared analogously to Example 10.0: (I-10a)

Ex- Starting Empirical Mass m.p. R_(f) ample R² R³ R^(4′) materials formula spectrum [° C.] value* 10.1 -F

—CH₂—NMe₂ 6.3 C₂₇H₂₆FN₃O₃ 460 [M+H]⁺ 250 0.65(A) 10.2 -F

—CH₂—NMe₂ 3.9 C₂₆H₂₄FN₃O₃ 444 [M−H]⁻ 278-282 0.10(B) 10.3 -F

—CH₂—NMe₂ 6.4 C₂₇H₂₆FN₃O₃ 458 [M−H]⁻ 198-200 0.20(C) 10.4 -F

—CH₂—NMe₂ 3.7 C₂₆H₂₄FN₃O₃ 444 [M−H]⁻ 212-216 0.30(D) 10.5 -F

3.12 C₃₁H₃₂FN₅O₄ 558 [M+H]⁺ 260-263 0.20(D) 10.6 -F

—N(SO₂Me)—(CH₂)₂—NMe₂ 3.11 C₂₈H₂₉FN₄O₅S 553 [M+H]⁺ 246-249 0.30(D) 10.7 -F

—N(Me)—(CO)—CH₃ 3.17 C₂₇H₂₄FN₃O₄ 474 [M+H]⁺ 286-290 0.60(E) 10.8 -F

3.18 C₃₂H₃₄FN₅O₄ 570 [M−H]⁻ 215-222 0.20(D) 10.9 -F

—N(SO₂Me)—(CH₂)₂—NMe₂ 3.19 C₂₉H₃₁FN₄O₅S 567 [M+H]⁺ 160-165 0.20(D) 10.10 -F

—N(COMe)—(CH₂)₃—NMe₂ 3.20 C₃₁H₃₃FN₄O₄ 545 [M+H]⁺ 153-158 0.15(D) 10.11 -F

3.21 C₃₁H₃₂FN₃O₅ 546 [M+H]⁺ 215-219 0.60(E) 10.12 -F

3.22 C₃₀H₂₉FN₄O₄ 529 [M+H]⁺ 179-186 0.25(E) 10.13 -F

3.23 C₂₈H₂₃FN₄O₃ 483 [M+H]⁺ 264-267 0.65(E) 10.14 -F

—SO₂Me 3.24 C₂₅H₂₁FN₂O₅S 481 [M+H]⁺ 146-155 0.70(E) 10.15 -F

3.27 C₂₉H₂₇FN₄O₄ 515 [M+H]⁺ 251 0.70(E) 10.16 -F

3.25 C₃₁H₃₂FN₅O₄ 558 [M+H]⁺ 234 0.10(E) 10.17 -F

—N(Me)—(CO)—CH₂—NMe₂ 3.28 C₂₈H₂₇FN₄O₄ 503 [M+H]⁺ 203 0.60(E) 10.18 -F

—N(Me)—(CO)—(CH₂)₄—NMe₂ 3.31 C₃₁H₃₃FN₄O₄ 545 [M+H]⁺ 251 n.d. 10.19 -F

-H 3.42 C₂₃H₁₇FN₂O₃ 387 [M−H]⁻ 130 0.60(E) 10.20 -F

—SO₂Me 3.43 C₂₄H₁₉FN₂O₅S 467 [M+H]⁺ 139 0.55(E) 10.21 -F

3.44 C₂₇H₂₁FN₄O₃ 469 [M+H]⁺ 157 0.35(E) 10.22 -F

—N(SO₂Me)—(CH₂)—(CO)—NMe₂ 3.45 C₂₈H₂₇FN₄O₆S 567 [M+H]⁺ 183 0.55(E) 10.23 -F

-H 3.32 C₂₃H₁₇FN₂O₃ 389 [M+H]⁺ 237-240 0.10(D) 10.24 -F

3.33 C₂₇H₂₁FN₄O₃ 469 [M+H]⁺ 259-265 0.15(D) 10.25 -F

—N(COMe)—(CH₂)₃—NMe₂ 3.41 C₃₀H₃₁FN₄O₄ 531 [M+H]⁺ 274-278 0.15(D) 10.26 -F

—N(Me)—(CO)—CH₂—NMe₂ 3.36 C₂₈H₂₇FN₄O₄ 503 [M+H]⁺ 258-264 0.20(D) 10.27 -F

3.34 C₂₉H₂₇FN₄O₄ 515 [M+H]⁺ 279-282 0.15(D) 10.28 -F

—SO₂Me 3.39 C₂₄H₁₉FN₂O₅S 467 [M+H]⁺ 260-266 0.35(F) 10.29 -F

—N(COMe)—CH₃ 3.37 C₂₆H₂₂FN₃O₄ 460 [M+H]⁺ 290-294 0.30(F) 10.30 -F

—N(SO₂Me)—CH₂—(CO)—NMe₂ 3.35 C₂₈H₂₇FN₄O₆S 567 [M+H]⁺ 238-242 0.30(F) 10.31 -F

—N(Me)—(CO)—(CH₂)₂—NMe₂ 3.38 C₂₉H₂₉FN₄O₄ 517 [M+H]⁺ 250-255 0.35(F) 10.32 -F

—N(Me)—(CO)—(CH₂)₃—NMe₂ 3.40 C₃₀H₃₁FN₄O₄ 531 [M+H]⁺ 184-190 0.25(F) 10.33 -F

3.48 C₃₂H₃₄FN₅O₄ 572 [M−H]⁻ 170-175 0.40(C) 10.34 -F

—N(SO₂Me)—(CH₂)₂—NMe₂ 3.26 C₂₈H₂₉FN₄O₅S 553 [M+H]⁺ 180 0.60(C) 10.35 -F

—N(SO₂Me)—(CH₂)₂—NMe₂ 3.49 C₂₉H₃₁FN₄O₅S 567 [M+H]⁺ 196-199 0.30(C) 10.36 -F

—N(Me)—(CO)—CH₂—NMe₂ 3.50 C₂₉H₂₉FN₄O₄ 517 [M+H]⁺ 150 0.20(C) 10.37 -F

—N(COMe)—(CH₂)₃—NMe₂ 3.51 C₃₁H₃₃FN₄O₄ 545 [M+H]⁺ 206-210 0.30(A) 10.38 -F

—N(Me)—(CO)—CH₂—NMe₂ 3.59 C₂₉H₂₉FN₄O₄ 517 [M+H]⁺ 231-236 0.60(A) 10.39 -F

—(CH₂)₂—NMe₂ 3.57 C₂₈H₂₈FN₃O₃ 474 [M+H]⁺ 218-222 0.50(A) 10.40 -F

—N(Me)—(CO)—(CH₂)₂—NMe₂ 3.58 C₃₀H₃₁FN₄O₄ 531 [M+H]⁺ 215-218 0.50(A) 10.41 -F

—(CH₂)₂—NMe₂ 3.60 C₂₈H₂₈FN₃O₃ 474 [M+H]⁺ 172-177 0.15(G) 10.42 -F

—N(COMe)—(CH₂)₂—NMe₂ 3.61 C₃₀H₃₁FN₄O₄ 531 [M+H]⁺ 230-234 0.50(A) 10.43 -F

—N(Me)—(CO)—(CH₂)₃—NMe₂ 3.62 C₃₁H₃₃FN₄O₄ 545 [M+H]⁺ 170-175 0.30(E) 10.44 -F

—N(Me)—(CO)—(CH₂)₄—NMe₂ 3.63 C₃₂H₃₅FN₄O₄ 559 [M+H]⁺ 142-146 0.10(G) 10.45 -F

3.64 C₂₈H₂₃FN₄O₃ 483 [M+H]⁺ 262-269 0.20(E) 10.46 -F

—N(Me)—(CO)—(CH₂)₄—NMe₂ 3.65 C₃₂H₃₅FN₄O₄ 559 [M+H]⁺ 234-236 0.30(A) 10.47 -F

-H 3.66 C₂₄H₁₉FN₂O₃ 403 [M+H]⁺ 231-233 0.20(A) 10.48 -F

3.67 C₂₉H₂₈FN₃O₃ 486 [M+H]⁺ 205-210 0.10(E) 10.49 -F

—CH₂—NEt₂ 3.68 C₂₉H₃₀FN₃O₃ 488 [M+H]⁺ 145-150 0.15(E) 10.50 -F

—CH₂—NH₂ 9.7 C₂₅H₂₂FN₃O₃ 430 [M−H]⁻ 280-285 0.05(H) 10.51 -F

—(CH₂)₂—NMe₂ 3.70 C₂₇H₂₆FN₃O₃ 460 [M+H]⁺ 273-276 0.15(E) 10.52 -F

—(CH₂)₂—NMe₂ 3.71 C₂₇H₂₆FN₃O₃ 460 [M+H]⁺ 230-235 0.05(E) 10.53 -Cl

—(CH₂)₂—NMe₂ 3.73 C₂₈H₂₈ClN₃O₃ 490/492 [M+H]⁺ 255-258 0.50(A) 10.54 -Cl

3.74 C₂₈H₂₃ClN₄O₃ 499/501 [M+H]⁺ 296-300 0.50(A) 10.55 -Cl

—CH₂—NMe₂ 3.75 C₂₇H₂₆ClN₃O₃ 476/478 [M+H]⁺ 228-230 0.50(A) 10.56 -F

3.77 C₃₀H₃₁FN₄O₃ 515 [M+H]⁺ 210-215 0.40(A) 10.57 -F

3.78 C₂₈H₂₃FN₄O₃ 483 [M+H]⁺ 240-245 0.50(A) 10.58 -F

—CH₂NMe—(CH₂)₂—NMe₂ 3.82 C₃₀H₃₃FN₄O₃ 517 [M+H]⁺ n.d. 0.30(I) 10.59 -F

3.79 C₃₀H₃₁FN₄O₃ 515 [M+H]⁺ 275 0.35(A) 10.60 -F

3.80 C₂₈H₂₃FN₄O₃ 483 [M+H]⁺ 280 0.55(A) 10.61 -F

3.83 C₂₉H₂₈ClN₃O₃ 502/504 [M+H]⁺ 260-266 0.50(A) 10.62 -F

—CH₂NMe—(CH₂)₂—NMe₂ 3.81 C₃₀H₃₃FN₄O₃ 517 [M+H]⁺ n.d. 0.05(E) 10.63 -F

-H 3.84 C₂₄H₁₉FN₂O₃ 403 [M+H]⁺ 110-112 0.60(K) 10.64 -F

—CH₂—NH₂ 9.8 C₂₅H₂₂FN₃O₃ 432 [M+H]⁺ 260-263 0.60(A) 10.65 -F

—CH₂—NHMe 9.9 C₂₆H₂₄FN₃O₃ 446 [M+H]⁺ 265-270 0.60(A) 10.66 -F

—CH₂—NMe₂ 3.87 C₂₆H₂₄FN₃O₄ 462 [M+H]⁺ 250 0.10(M) 10.67 -F

—CH₂—NMe₂ 3.88 C₂₆H₂₄FN₃O₄ 462 [M+H]⁺ 247 0.15(M) 10.68 -Br

3.90 C₂₉H₂₈BrN₃O₃ 546/548 [M+H]⁺ 290-293 0.30(E) 10.69 -Br

—CH₂—NMe₂ 3.91 C₂₇H₂₆BrN₃O₃ 520/522 [M+H]⁺ 243-246 0.25(E) 10.70 -Br

—CH₂—NEt₂ 3.92 C₂₉H₃₀BrN₃O₃ 548/550 [M+H]⁺ 252-255 0.35(E) *Eluent mixtures: (A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1 (B): silica gel, methylene chloride/methanol = 8:2 (C): silica gel, methylene chloride/methanol = 5:1 (D): reversed phase RP8, methanol/sodium chloride solution (5%) = 3:2 (E): silica gel, methylene chloride/methanol = 9:1 (F): reversed phase RP8, methanol/sodium chloride solution (5%) = 7:3 (G): silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 (H): alumina, methylene chloride/methanol = 19:1 (I): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:2 (K): silica gel, petroleum ether/ethyl acetate = 1:1 (M): silica gel, methylene chloride/methanol = 4:1

The following compounds of the formula I-10b are prepared analogously to Example 10.0: (I-10b)

Example R² R³ R⁴′ Starting materials Empirical formula Mass spectrum m.p. [° C.] R_(f)-value* 10.71 —F

—CH₂—NMe₂ 3.93 C₂₇H₂₆FN₃O₃ 460 [M + H]⁺ 150 0.20 (A) 10.72 —F

—CH₂—NMe₂ 3.94 C₂₇H₂₆FN₃O₃ 460 [M + H]⁺ 105-109 0.30 (B) 10.73 —Cl

—CH₂—NMe₂ 3.95 C₂₇H₂₆ClN₃O₃ 476/478 [M + H]⁺ 230-235 0.50 (C) *Eluent mixtures: (A): silica gel, methylene chloride/methanol = 5:1 (B): silica gel, methylene chloride/methanol = 9:1 (C): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1

EXAMPLE 11.0

3-Z-[1-(4-Dimethylaminomethylanilino)-1-(3-(2-carbamoylethyl)phenyl)methylene]-6-chloro-2-indolinone

480 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (starting material 10.0), 350 mg of TBTU, 150 mg of HOBt and 420 ml of triethylamine are dissolved in 10 ml of dimethylformamide, and 620 mg of N-hydroxysuccinimide ammonium salt are added. The mixture is stirred at room temperature for 20 hours. After removal of the solvent under reduced pressure, the residue is suspended in a little ethyl acetate and water, filtered off and washed with water. The residue is purified on an alumina column (activity 2-3) using the mobile phase methylene chloride/ethanol 20:1. The product is recrystallized from diethyl ether and dried under reduced pressure at 100° C.

Yield: 370 mg (78% of theory),

R_(f) value: 0.40 (alumina, methylene chloride/ethanol=20:1)

m.p. 222-225° C.

C₂₇H₂₇ClN₄O₂

Mass spectrum: m/z=475/477 [M+H]⁺

The following compounds of the formula I-11 are prepared analogously to Example 11.0: (I-11)

Starting Empirical Mass Example R² R³ R⁴′ materials formula spectrum m.p. [° C.] R_(f) value* 11.1 —Cl

—CH₂—NMe₂ 10.0** C₂₈H₂₉ClN₄O₂ 489/491 [M + H]⁺ 223-225 0.50 (A) 11.2 —F

—CH₂—NMe₂ 10.1** C₂₈H₂₉FN₄O₂ 473 [M + H]⁺ 148-150 0.40 (B) 11.3 —F

—CH₂—NMe₂ 10.2*** C₂₈H₂₉FN₄O₂ 473 [M + H]⁺ 98-103 0.30 (C) 11.4 —F

—CH₂—NMe₂ 10.3 C₂₇H₂₇FN₄O₂ 459 [M + H]⁺ 223-225 0.50 (A) 11.5 —F

—CH₂—NMe₂ 10.3** C₂₈H₂₉FN₄O₂ 473 [M + H]⁺ 210-213 0.70 (A) 11.6 —F

—CH₂—NMe₂ 10.3*** C₂₉H₃₁FN₄O₂ 487 [M + H]⁺ 213-215 0.80 (A) 11.7 —F

—CH₂—NMe₂ 10.2 C₂₆H₂₅FN₄O₂ 443 [M − H]⁻ 115-120 0.25 (C) 11.8 —F

—CH₂—NMe₂ 10.2** C₂₇H₂₇FN₄O₂ 457 [M − H]⁻ 222-225 0.25 (C) 11.9 —F

—CH₂—NMe₂ 10.4 C₂₆H₂₅FN₄O₂ 443 [M − H]⁻ 143-146 0.40 (D) 11.10 —F

—CH₂—NMe₂ 10.1*** C₂₉H₃₁FN₄O₂ 487 [M + H]⁺ 198-200 0.60 (B) 11.11 —F

—CH₂—NMe₂ 10.1**** C₃₂H₃₆FN₅O₂ 542 [M + H]⁺ 175 0.60 (B) 11.12 —F

10.5 C₃₁H₃₃FN₆O₃ 557 [M + H]⁺ 150-156 0.40 (E) 11.13 —F

—N(SO₂Me)—(CH₂)₂—NMe₂ 10.6 C₂₈H₃₀FN₅O₄S 552 [M + H]⁺ 197-199 0.50 (D) 11.14 —F

—CH₂—NMe₂ 10.4*** C₂₈H₂₉FN₄O₂ 473 [M + H]⁺ 147-152 0.35 (D) 11.15 —F

—CH₂—NMe₂ 10.4** C₂₇H₂₇FN₄O₂ 459 [M + H]⁺ 208-214 0.35 (D) 11.16 —F

—N(SO₂Me)—(CH₂)₂—NMe₂ 10.6** C₂₉H₃₂FN₅O₄S 566 [M + H]⁺ 218-222 0.70 (F) 11.17 —F

—N(SO₂Me)—(CH₂)₂—NMe₂ 10.6*** C₃₀H₃₄FN₅O₄S 580 [M + H]⁺ 199-205 0.40 (C) 11.18 —F

10.5** C₃₂H₃₅FN₆O₃ 571 [M + H]⁺ 155-160 0.20 (C) 11.19 —F

—N(Me)—(CO)—CH₃ 10.7** C₂₈H₂₇FN₄O₃ 487 [M + H]⁺ 137-145 0.50 (C) 11.20 —F

10.8** C₃₃H₃₇FN₆O₃ 585 [M + H]⁺ 211-219 0.40 (C) 11.21 —F

—N(SO₂Me)—(CH₂)₂—NMe₂ 10.9** C₃₀H₃₄FN₅O₄S 578 [M − H]⁻ 192-200 0.50 (C) 11.22 —F

10.11** C₃₂H₃₅FN₄O₄ 559 [M + H]⁺ 180-187 0.50 (C) 11.23 —F

10.13** C₂₉H₂₆FN₅O₂ 496 [M + H]⁺ 262-266 0.40 (C) 11.24 —F

—SO₂Me 10.14** C₂₆H₂₄FN₃O₄S 494 [M + H]⁺ 180-188 0.60 (C) 11.25 —F

10.12** C₃₁H₃₂FN₅O₃ 542 [M + H]⁺ 226-230 0.50 (C) 11.26 —F

10.16** C₃₂H₃₅FN₆O₃ 571 [M + H]⁺ 213 0.10 (G) 11.27 —F

10.15** C₃₀H₃₀FN₅O₃ 528 [M + H]⁺ 245 0.40 (G) *Eluent mixtures: (A): silica gel, methylene chloride/methanol/ammonia = 5:1:0.01 (B): alumina, methylene chloride/ethanol = 20:1 (C): silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 (D): silica gel, methylene chloride/methanol/ammonia = 6:1:0.1 (E): silica gel, methylene chloride/methanol/ammonia = 5:1:0.1 (F): silica gel, methylene chloride/methanol/ammonia = 7:1:0.1 (G): silica gel, methylene chloride/methanol = 9:1 **using methylammonium chloride as base equivalent ***using dimethylammonium chloride as base equivalent ****using piperidine hydrochloride as base equivalent

EXAMPLE 12.0

3-Z-[1-(4-Dimethylaminomethylanilino)-1-(4-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone

100 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-aminomethylphenyl)-methylene]-6-chloro-2-indolinone (starting material 7.0) are dissolved in 5 ml of methylene chloride and 5 ml of pyridine, and 20 μl of acetyl chloride are added at 0° C. The mixture is stirred at 0° C. for 10 minutes and at room temperature for a further 4 hours. Another 20 μl of acetyl chloride are then added, and the mixture is stirred at room temperature for 12 hours. After this time, the solvent is removed under reduced pressure and the residue is taken up in methylene chloride and washed with water. The aqueous phase is extracted twice with methylene chloride and the combined organic phases are dried over sodium sulphate. The solvent is removed using a rotary evaporator and the residue is washed with ether.

Yield: 51 mg (47% of theory),

R_(f) value: 0.30 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01)

m.p. 219-220° C.

C₂₇H₂₇ClN₄O₂

Mass spectrum: m/z=473/475 [M−H]⁻

The following compounds of the formula I-12 are prepared analogously to Example 12.0: (I-12)

Ex- Starting Empirical Mass ample R² R³ R⁴′ materials formula spectrum m.p. [° C.] R_(f)-value* 12.1 —Cl

8.0 C₃₂H₃₅ClN₆O₃ 585/587 [M − H]⁻ 252-255 0.25 (B) 12.2 —Cl

—CH₂—NMe₂ 7.0 C₃₂H₂₉ClN₄O₂ 535/537 [M − H]⁻ 238 (decomp.) 0.45 (B) 12.3 —Cl

8.0 C₃₇H₃₇ClN₆O₃ 647/649 [M − H]⁻ 282-284 0.40 (B) 12.4 —F

—CH₂—NMe₂ 9.0 C₂₇H₂₇FN₄O₂ 457 [M − H]⁻ 245-250 0.40 (C) 12.5 —F

—CH₂—NMe₂ 9.0 C₂₈H₂₉FN₄O₂ 471 [M − H]⁻ 212-214 0.35 (D) 12.6 —F

—CH₂—NMe₂ 9.0 C₃₂H₂₉FN₄O₂ 519 [M − H]⁻ 237-240 0.40 (D) 12.7 —F

—CH₂—NMe₂ 9.0 C₃₃H₃₁FN₄O₂ 533 [M − ]⁻ 187-190 0.30 (D) 12.8 —F

—CH₂—NMe₂ 9.1 C₂₈H₂₉FN₄O₂ 471 [M − H]⁻ 234-237 0.30 (D) 12.9 —F

—CH₂—NMe₂ 9.1 C₃₃H₃₁FN₄O₂ 533 [M − H]⁻ 144-150 0.45 (C) 12.10 —F

—CH₂—NMe₂ 9.1 C₂₉H₃₁FN₄O₂ 485 [M − H]⁻ 235-237 0.25 (D) 12.11 —F

—CH₂—NMe₂ 9.1 C₃₄H₃₃FN₄O₂ 547 [M − H]⁻ 217-220 0.30 (D) 12.12 —F

—CH₂—NMe₂ 9.2 C₂₇H₂₇FN₄O₂ 457 [M − H]⁻ 112-120 0.25 (D) 12.13 —F

—CH₂—NMe₂ 9.2 C₂₈H₂₉FN₄O₂ 586 [M + H]⁺ 176-180 0.30 (D) 12.14 —F

—CH₂—NMe₂ 9.2 C₃₃H₃₁FN₄O₂ 535 [M + H]⁺ 80-85 0.35 (D) 12.15 —F

9.3 C₃₂H₃₅FN₆O₃ 569 [M − H]⁻ 230-235 0.35 (D) 12.16 —F

9.3 C₃₃H₃₇FN₆O₃ 583 [M − H]⁻ 205-210 0.30 (D) 12.17 —F

9.3 C₃₈H₃₉FN₆O₃ 645 [M − H]⁻ 217-220 0.35 (D) 12.18 —F

9.6 C₃₄H₃₇FN₆O₃ 597 [M + H]⁺ 209-212 0.30 (D) 12.19 —F

9.6 C₃₅H₃₉FN₆O₃ 611 [M + H]⁺ 190-193 0.30 (D) 12.20 —F

9.6 C₃₆H₃₆FN₇O₃ 634 [M + H]⁺ 160-163 0.30 (D) 12.21 —F

9.6 C₃₇H₄₃FN₆O₃ 639 [M + H]⁺ 223-227 0.30 (D) 12.22 —F

9.6 C₃₆H₃₆FN₇O₃ 634 [M + H]⁺ 170-175 0.25 (D) 12.23 —F

9.6 C₃₄H₃₉FN₆O₃ 599 [M + H]⁺ 194-196 0.20 (D) 12.24 —F

9.6 C₃₅H₄₁FN₆O₃ 613 [M + H]⁺ 197-200 0.70 (E) 12.25 —F

9.6 C₃₈H₄₅FN₆O₃ 653 [M + H]⁺ 130-135 0.75 (E) 12.26 —F

9.6 C₃₃H₃₇FN₆O₄ 601 [M + H]⁺ 155-159 0.60 (E) 12.27 —F

9.6 C₃₈H₃₉FN₆O₄ 663 [M + H]⁺ 168-172 0.35 (C) 12.28 —F

9.6 C₃₆H₄₃FN₆O₃ 627 [M + H]⁺ 85-90 0.35 (C) 12.29 —F

9.6 C₃₅H₃₅FN₆O₃S 639 [M + H]⁺ 170-175 0.25 (C) 12.30 —F

9.6 C₃₅H₄₁FN₆O₃ 613 [M + H]⁺ 242-245 0.30 (C) 12.31 —F

9.6 C₃₅H₃₅FN₆O₄ 623 [M + H]⁺ 155-160 0.65 (F) 12.32 —F

9.6 C₃₂H₃₅FN₆O₃ 571 [M + H]⁺ 190-195 0.60 (F) 12.33 —F

9.6 C₃₃H₃₇FN₆O₃ 585 [M + H]⁺ 203-209 0.65 (E) 12.34 —F

9.6 C₃₇H₃₇FN₆O₃ 633 [M + H]⁺ 145-150 0.60 (F) 12.35 —F

9.6 C₃₈H₃₉FN₆O₃ 647 [M + H]⁺ 148-151 0.65 (F) 12.36 —F

—CH₂—NMe₂ 9.0 C₂₉H₂₉FN₄O₂ 485 [M + H]⁺ 216-220 0.35 (D) 12.37 —F

—CH₂—NMe₂ 9.0 C₃₀H₃₁FN₄O₂ 499 [M + H]⁺ 214-217 0.35 (D) 12.38 —F

—CH₂—NMe₂ 9.0 C₃₁H₂₈FN₅O₂ 522 [M + H]⁺ 205-210 0.35 (D) 12.39 —F

—CH₂—NMe₂ 9.0 C₃₂H₃₅FN₄O₂ 527 [M + H]⁺ 235-237 0.35 (D) 12.40 —F

—CH₂—NMe₂ 9.0 C₃₁H₂₈FN₅O₂ 520 [M − H]⁻ 135-140 0.20 (D) 12.41 —F

—CH₂—NMe₂ 9.0 C₂₉H₃₁FN₄O₂ 487 [M + H]⁺ 210-215 0.20 (D) 12.42 —F

—CH₂—NMe₂ 9.0 C₃₀H₃₃FN₄O₂ 501 [M + H]⁺ 202-206 0.25 (D) 12.43 —F

—CH₂—NMe₂ 9.0 C₃₃H₃₇FN₄O₂ 541 [M + H]⁺ 198-203 0.35 (D) 12.44 —F

—CH₂—NMe₂ 9.0 C₂₈H₂₉FN₄O₃ 489 [M + H]⁺ 173-177 0.35 (D) 12.45 —F

—CH₂—NMe₂ 9.0 C₃₃H₃₁FN₄O₃ 549 [M − H]⁻ 202-207 0.50 (C) 12.46 —F

—CH₂—NMe₂ 9.0 C₃₁H₃₅FN₄O₂ 513 [M − H]⁻ 203-209 0.45 (C) 12.47 —F

—CH₂—NMe₂ 9.0 C₃₀H₂₇FN₄O₂S 527 [M + H]⁺ 245-250 0.35 (C) 12.48 —F

—CH₂—NMe₂ 9.0 C₃₀H₃₃FN₄O₂ 501 [M + H]⁺ 248-252 0.45 (C) 12.49 —F

—CH₂—NMe₂ 9.0 C₃₀H₂₇FN₄O₃ 511 [M + H]⁺ 216-219 0.30 (C) 12.50 —F

—CH₂—NMe₂ 9.0 C₃₁H₂₈FN₅O₂ 522 [M + H]⁺ 167-170 0.20 (D) *Eluent mixtures: (A): silica gel, methylene chloride/ethanol/ammonia = 20:1:0.01 (B): silica gel, methylene chloride/methanol/ammonia = 9:1:0.01 (C): alumina, methylene chloride/methanol = 19:1 (D): silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 (E): silica gel, methylene chloride/methanol/ammonia = 8:2:0.2 (F): alumina, methylene chloride/methanol = 9:1

Alternatively, the following acylating agents were used:

benzoyl chloride, propionyl chloride, phenylacetyl chloride, cyclopropanecarbonyl chloride, cyclobutanecarbonyl chloride, pyridin-2-ylcarbonyl chloride, pyridin-3-ylcarbonyl chloride, pyridin-4-ylcarbonyl chloride, cyclohexylcarbonyl chloride, isobutyryl chloride, 3-methylbutyryl chloride, cyclohexylmethylcarbonyl chloride, methoxyacetyl chloride, 2-methoxybenzoyl chloride, tert-butylacetyl chloride, thiophene-2-carbonyl chloride, pivaloyl chloride, 2-furoyl chloride

EXAMPLE 13.0

3-Z-[1-(4-Trimethylammoniummethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone iodide

200 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 10.1) are dissolved in 40 ml of acetone, and 250 ml of methyl iodide are added. The mixture is stirred at room temperature for 20 hours. After this time, the resulting residue is filtered off with suction. The product is dried at 80° C. under reduced pressure.

Yield: 200 mg (83% of theory),

R_(f) value: 0.50 (reversed phase RP8, methanol/sodium chloride solution (5%)=4:1)

m.p. 210° C.

C₂₈H₂₉FN₃O₃I

Mass spectrum: m/z=474 [M+H]⁺

The following compound of the formula I-13 is prepared analogously to Example 13.0: (I-13)

Example R² R³ R⁴′ Starting materials Empirical formula Mass spectrum m.p. [° C.] R_(f) value* 13.1 —F

10.3 C₂₈H₂₉FN₃O₃I 474 [M + H]⁺ 150 0.50 (A) *Eluent mixture: (A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1

EXAMPLE 14.0

3-Z-[1-(4-Guanidinomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone iodide

170 mg of 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 10.50) are dissolved in 20 ml of tetrahydrofuran, and 390 mg of 3,5-dimethylpyrazole-1-carboxamidine nitrate and 330 ml of diethylisopropylamine are added. The mixture is stirred under reflux for 10 hours. After this time, the solvent is concentrated, water is added and the resulting residue is filtered off with suction. The product is dried at 80° C.

Yield: 150 mg (81% of theory),

R_(f) value: 0.40 (silica gel, methylene chloride/methanol/acetic acid=5:1:0.1)

m.p. 290° C.

C₂₆H₂₄FN₅O₃

Mass spectrum: m/z=474 [M+H]⁺

The following compound of the formula I-14 is prepared analogously to Example 14.0: (I-14)

Example R² R³ R⁴′ Starting materials Empirical formula Mass spectrum m.p. [° C.] R_(f) value* 14.1 —F

10.64 C₂₆H₂₄FN₅O₃ 474 [M + H]⁺ 305 0.70 (A) *Eluent mixture: (A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1

EXAMPLE 15

Dry vial with 75 mg of active compound per 10 ml

Composition: Active compound 75.0 mg Mannitol 50.0 mg Water for injection ad 10.0 ml Preparation:

Active compound and mannitol were dissolved in water. After filling, the product is freeze-dried. The ready-to-use solution is obtained by dissolving the product in water for injection.

EXAMPLE 16

Dry vial with 35 mg of active compound per 2 ml

Composition: Active compound 35.0 mg Mannitol 100.0 mg Water for injection ad 2.0 ml Preparation:

Active compound and mannitol were dissolved in water. After filling, the product is freeze-dried. The ready-to-use solution is obtained by dissolving the product in water for injection.

EXAMPLE 17

Tablet with 50 mg of active compound

Composition: (1) Active compound  50.0 mg (2) Lactose  98.0 mg (3) Maize starch  50.0 mg (4) Polyvinylpyrrolidone  15.0 mg (5) Magnesium stearate  2.0 mg 215.0 mg Preparation:

(1), (2) and (3) are mixed and granulated using an aqueous solution of (4). (5) is added to the dried granules. From this mixture, biplanar tablets having a facet on both sides and being partially scored on one side are pressed.

Diameter of the tablets: 9 mm.

EXAMPLE 18

Tablet with 350 mg of active compound

Composition: (1) Active compound 350.0 mg (2) Lactose 136.0 mg (3) Maize starch  80.0 mg (4) Polyvinylpyrrolidone  30.0 mg (5) Magnesium stearate  4.0 mg 600.0 mg Preparation:

(1), (2) and (3) are mixed and granulated using an aqueous solution of (4). (5) is added to the dried granules. From this mixture, biplanar tablets having a facet on both sides and being partially scored on one side are pressed.

Diameter of the tablets: 12 mm.

EXAMPLE 19

Capsules with 50 mg of active compound

Composition: (1) Active compound  50.0 mg (2) Maize starch, dried  58.0 mg (3) Lactose, powdered  50.0 mg (4) Magnesium stearate  2.0 mg 160.0 mg Preparation:

(1) is ground with (3). This ground material is, with vigorous mixing, added to the mixture of (2) and (4).

This powder mixture is, in a capsule filling machine, filled into hard gelatin capsules size 3.

EXAMPLE 20

Capsules with 350 mg of active compound

Composition: (1) Active compound 350.0 mg (2) Maize starch, dried  46.0 mg (3) Lactose, powdered  30.0 mg (4) Magnesium stearate  4.0 mg 430.0 mg Preparation:

(1) is ground with (3). This ground material is, with vigorous mixing, added to the mixture of (2) and (4).

This powder mixture is, in a capsule filling machine, filled into hard gelatin capsules size 0.

EXAMPLE 21

Suppositories with 100 mg of active compound

1 suppository contains: Active compound  100.0 mg Polyethylene glycol (MW 1500)  600.0 mg Polyethylene glycol (MW 6000)  460.0 mg Polyethylene sorbitan monostearate  840.0 mg 2000.0 mg Preparation:

The polyethylene glycol is melted together with polyethylene sorbitan monostearate. At 40° C., the ground active substance is homogeneously dispersed in the melt. The melt is cooled to 38° C. and poured into slightly pre-cooled suppository moulds.

Analogously to the examples above, it is possible to prepare the following compounds:

-   (1)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (2)     3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (3)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (4)     3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (5)     3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (6)     3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (7)     3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (8)     3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (9)     3-Z-[1-(4-methylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (10)     3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (11)     3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (12)     3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (13)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (14)     3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (15)     3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (16)     3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (17)     3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (18)     3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (19)     3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (20)     3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (21)     3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (22)     3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (23)     3-Z-[1-(4-(N-(2-dimethylaminoethyl-carbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (24)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (25)     3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (26)     3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (27)     3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (28)     3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (29)     3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (30)     3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (31)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenylmethylene]-6-chloro-2-indolinone -   (32)     3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (33)     3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (34)     3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (35)     3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (36)     3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (37)     3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (38)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (39)     3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (40)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (41)     3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (42)     3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (43)     3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (44)     3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (45)     3-Z-[1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (46)     3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (47)     3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (48)     3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (49)     3-Z-(1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (50)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (51)     3-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (52)     3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (53)     3-Z-[1-(3-(methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (54)     3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (55)     3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (56)     3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (57)     3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (58)     3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (59)     3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (60)     3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (61)     3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (62)     3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (63)     3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (64)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (65)     3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (66)     3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (67)     3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (68)     3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (69)     3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (70)     3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (71)     3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (72)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenylmethylene]-6-chloro-2-indolinone -   (73)     3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (74)     3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (75)     3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (76)     3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene)-6-chloro-2-indolinone -   (77)     3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (78)     3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (79) 3-Z-[1-(4-(imidazol-1-yl     methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone -   (80)     3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (81)     3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (82)     3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (83)     3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (84)     3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (85)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (86)     3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (87)     3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (88)     3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (89)     3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (90)     3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (91)     3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (92)     3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (93)     3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (94)     3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (95)     3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (96)     3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (97)     3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (98)     3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene)-6-fluoro-2-indolinone -   (99)     3-Z-(1-(4-(piperazin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (100)     3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (101)     3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (102)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (103)     3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (104)     3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (105)     3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene)-6-fluoro-2-indolinone -   (106)     3-Z-[1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (107)     3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (108)     3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (109)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (110)     3-Z-[1-(3-(methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (111)     3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (112)     3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (113)     3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (114)     3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (115)     3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (116)     3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (117)     3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (118)     3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (119)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (120)     3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (121)     3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (122)     3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (123)     3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (124)     3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (125)     3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (126)     3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (127)     3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (128)     3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (129)     3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone -   (130)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (131)     3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (132)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (133)     3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (134)     3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (135)     3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (136)     3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (137)     3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (138)     3-Z-[1-(4-methylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (139)     3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (140)     3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (141)     3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (142)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (143)     3-Z-1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (144)     3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (145)     3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (146)     3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (147)     3-Z-(1-(3-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (148)     3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (149)     3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (150)     3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (151)     3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (152)     3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (153)     3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (154)     3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (155)     3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (156)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (157)     3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (158)     3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (159)     3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (160)     3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (161)     3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (162)     3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (163)     3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (164)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-phenylmethylene]-6-bromo-2-indolinone -   (165)     3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (166)     3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (167)     3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (168)     3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (169)     3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (170)     3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (171)     3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (172)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (173)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (174)     3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (175)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (176)     3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (177)     3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (178)     3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (179)     3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (180)     3-Z-[1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (181)     3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (182)     3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (183)     3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (184)     3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (185)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (186)     3-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (187)     3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (188)     3-Z-[1-(3-(methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (189)     3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (190)     3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (191)     3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (192)     3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (193)     3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (194)     3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (195)     3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (196)     3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (197)     3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (198)     3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (199)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (200)     3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (201)     3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (202)     3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (203)     3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (204)     3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (205)     3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (206)     3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (207)     3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenylmethylene]-6-bromo-2-indolinone -   (208)     3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (209)     3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (210)     3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (211)     3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (212)     3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (213)     3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (214) 3-Z-[1-(4-(imidazol-1-yl     methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone -   (215)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-6-fluoro-2-indolinone -   (216)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylamino-phenyl)-methylene]-6-fluoro-2-indolinone -   (217)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl-carboxymethylamino)phenyl)methylene]-6-fluoro-2-indolinone -   (218)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyl-carboxymethylamino)phenyl)methylene]-6-fluoro-2-indolinone -   (219)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)-methylene]-6-chloro-2-indolinone -   (220)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)-methylene]-6-chloro-2-indolinone -   (221)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-6-chloro-2-indolinone -   (222)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylaminophenyl)-methylene]-6-chloro-2-indolinone -   (223)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl-carboxymethylamino)phenyl)methylene]-6-chloro-2-indolinone -   (224)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyl-carboxymethylamino)phenyl)methylene]-6-chloro-2-indolinone -   (225)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)-methylene]-6-bromo-2-indolinone -   (226)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)-methylene]-6-bromo-2-indolinone -   (227)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-6-bromo-2-indolinone -   (228)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylaminophenyl)-methylene]-6-bromo-2-indolinone -   (229)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl-carboxymethylamino)phenyl)methylene]-6-bromo-2-indolinone -   (230)     3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyl-carboxymethylamino)phenyl)methylene]-6-bromo-2-indolinone     In the tables above, -   Me is methyl, -   Et is ethyl, -   Pr is propyl, -   nPr is n-propyl, -   iPr is isopropyl, -   nBu is n-butyl, -   tBu is tert-butyl and -   Bn is benzyl. 

1. A compound of the formula

in which X is an oxygen atom, R¹ is a hydrogen atom, R² is a fluorine, chlorine or bromine atom or a cyano group, R³ is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C₁₋₃-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or 4-position by a fluorine, chlorine or bromine atom, by a cyano group, by a C₁₋₃-alkoxy or C₁₋₂-alkyl-carbonyl-amino group, by a cyano-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyl, carboxy-C₁₋₄-alkoxy, carboxy-C₁₋₃-alkylamino, carboxy-C₁₋₃-alkyl-N-(C₁₋₃-alkyl)-amino, C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl, C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy, C-4-alkoxy-carbonyl-C₁₋₃-alkylamino, C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl-N-(C₁₋₃-alkyl)-amino, amino-C₁₋₃-alkyl, amino-carbonyl-C₁₋₃-alkyl, (C₁₋₂-alkylamino)-carbonyl-C₁₋₃-alkyl, di-(C₁₋₂-alkyl)-amino-carbonyl-C₁₋₃-alkyl, (C₁₋₂-alkyl-carbonyl)-amino-C₁₋₃-alkyl, (C₁₋₄-alkoxy-carbonyl)-amino-C₁₋₃-alkyl, (C₃₋₆-alkyl-carbonyl)-amino-C₁₋₃-alkyl, (phenyl-carbonyl)-amino-C₁₋₃-alkyl, (C₃₋₆-cycloalkyl-carbonyl)-amino-C₁₋₃-alkyl, (C₃₋₆-cycloalkyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl, (thiophen-2-yl-carbonyl)-amino-C₁₋₃-alkyl, (furan-2-yl-carbonyl)-amino-C₁₋₃-alkyl, (phenyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl, (2-(C₁₋₄-alkoxy)-benzoyl-carbonyl)-amino-C₁₋₃-alkyl, (pyridin-2-yl-carbonyl)-amino-C₁₋₃-alkyl, (pyridin-3-yl-carbonyl)-amino-C₁₋₃-alkyl-, (pyridin-4-yl-carbonyl)-amino-C₁₋₃-alkyl- or C₁₋₃-alkyl-piperazin-1-yl-carbonyl-C₁₋₃-alkyl group, by a carboxy-C₂₋₃-alkenyl, aminocarbonyl-C₂₋₃-alkenyl, (C₁₋₃-alkylamino)-carbonyl-C₂₋₃-alkenyl, di-(C₁₋₃-alkyl)-amino-carbonyl-C₂₋₃-alkenyl or C₁₋₄-alkoxy-carbonyl-C₂₋₃-alkenyl group, where the substituents may be identical or different, R⁴ is a phenyl group or a phenyl group which is monosubstituted by a C₁₋₃-alkyl group which is terminally substituted by an amino, guanidino, mono- or di-(C₁₋₂-alkyl)-amino-, N-[ω-di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl]-N-(C₁₋₃-alkyl)-amino, N-methyl-(C₃₋₄-alkyl)-amino, N-(C₁₋₃-alkyl)-N-benzylamino, N-(C₁₋₄-alkoxycarbonyl)-amino, N-(C₁₋₄-alkoxycarbonyl)-C₁₋₄-alkylamino, 4-(C₁₋₃-alkyl)-piperazin-1-yl, imidazol-1-yl, pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, thiomorpholin-4-yl group, by a di-(C₁₋₃-alkyl)-amino-(C₁₋₃-alkyl)-sulphonyl, 2-[di-(C₁₋₃-alkyl)-amino]-ethoxy, 4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl, {ω-[di-(C₁₋₃-alkyl)-amino]-(C₂₋₃-alkyl)}-N-(C₁₋₃-alkyl)-amino-carbonyl, 1-(C₁₋₃-alkyl)imidazol-2-yl, (C₁₋₃-alkyl)-sulphonyl group, or by a group of the formula

in which R⁷ is a C: ₂-alkyl, C₁₋₂-alkyl-carbonyl, di-(C₁₋₂-alkyl)-amino-carbonyl-C₁₋₃-alkyl or C₁₋₃-alkylsulphonyl group and R⁸ is C₁₋₃-alkyl, ω-[di-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl, ω-[mono-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl group, or a (C₁₋₃-alkyl)-carbonyl, (C₄₋₆-alkyl)-carbonyl or carbonyl-(C₁₋₃-alkyl) group which is terminally substituted by a di-(C₁₋₂-alkyl)-amino, piperazin-1-yl or 4-(C₁₋₃-alkyl)-piperazin-1-yl group, where all dialkylamino groups present in the radical R⁴ may also be present in quaternized form, for example as an N-methyl-(N,N-dialkyl)-ammonium group, where the counterion is preferably selected from the group consisting of iodide, chloride, bromide, methylsulphonate, para-toluenesulphonate and trifluoroacetate, R⁵ is a hydrogen atom and R⁶ is a hydrogen atom, where the abovementioned alkyl groups include linear and branched alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavable radical or may be present in the form of a prodrug radical, for example in the form of a group which can be converted in vivo into a carboxyl group or in the form of a group which can be converted in vivo into an imino or amino group, and its tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof.
 2. A compound of the formula I according to claim 1 in which X, R¹, R², R⁴, R⁵ and R⁶ are as defined in claim 1 and R³ is a phenyl group which is substituted by a C₁₋₂-alkyl-carbonyl-amino group, by a carboxy-C₁₋₃-alkyl, carboxy-C₁₋₄-alkoxy, C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl, C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy, aminocarbonyl-C₁₋₃-alkyl, (C₁₋₂-alkylamino)-carbonyl-C₁₋₃-alkyl, di-(C₁₋₂-alkyl)-aminocarbonyl-C₁₋₃-alkyl, (C₁₋₂-alkyl-carbonyl)-amino-C₁₋₃-alkyl, (C₁₋₄-alkoxy-carbonyl)-amino-C₁₋₃-alkyl, (phenyl-carbonyl)-amino-C₁₋₃-alkyl, (C₃₋₆-cycloalkyl-carbonyl)-amino-C₁₋₃-alkyl, (C₃₋₆-cycloalkyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl, (thiophen-2-yl-carbonyl)-amino-C₁₋₃-alkyl, (furan-2-yl-carbonyl)-amino-C₁₋₃-alkyl, (phenyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl, (2-(C₁₋₄-alkoxy)-benzoyl-carbonyl)-amino-C₁₋₃-alkyl, (pyridin-2-yl-carbonyl)-amino-C₁₋₃-alkyl, (pyridin-3-yl-carbonyl)-amino-C₁₋₃-alkyl, (pyridin-4-yl-carbonyl)-amino-C₁₋₃-alkyl or C₁₋₃-alkyl-piperazin-1-yl-carbonyl-C₁₋₃-alkyl group, by an aminocarbonyl-C₂₋₃-alkenyl, (C₁₋₃-alkylamino)-carbonyl-C₂₋₃-alkenyl, di-(C₁₋₃-alkyl)-amino-carbonyl-C₂₋₃-alkenyl or C₁₋₄-alkoxy-carbonyl-C₂₋₃-alkenyl group.
 3. A compound of the formula I according to claim 1 in which X, R¹, R², R⁴, R⁵ and R⁶ are as defined in claim 1 and R³ is a phenyl group substituted by a carboxy-C₁₋₃-alkyl or C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl group.
 4. A compound of the formula I according to any of claims 1 to 3, in which X, R¹, R³, R⁴, R⁵ and R⁶ are as defined in any of claims 1 to 3 and R² is a fluorine or chlorine atom.
 5. A compound of the formula I according to claim 1, selected from the following group: (a) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (b) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (c) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (d) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (e) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (f) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (g) 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (h) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (i) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (j) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (k) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (l) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (m) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (n) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (o) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (p) 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (q) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone and their salts.
 6. A physiologically acceptable salt of a compound according to any one of claims 1, 2, 3 or
 5. 7. A physiologically acceptable salt of a compound according to claim
 4. 8. A medicament comprising a compound of the formula I according to any one of claims 1, 2, 3 or 5, and one or more inert carrier materials and/or diluents.
 9. A medicament, comprising a compound of the formula I according to claim 4, and one or more inert carrier materials and/or diluents.
 10. A medicament, comprising a physiologically acceptable salt according to claim 6, and one or more inert carrier materials and/or diluents.
 11. A medicament, comprising a physiologically acceptable salt according to claim 7, and one or more inert carrier materials and/or diluents.
 12. A method for treating excessive or abnormal cell proliferation comprising administering a compound of the formula I according to any one of claims 1, 2, 3, or
 5. 13. A method for treating excessive or abnormal cell proliferation comprising administering a compound of the formula I according to claim
 4. 14. A method for treating excessive or abnormal cell proliferation comprising administering a physiologically acceptable salt according to claim
 6. 15. A method for treating excessive or abnormal cell proliferation comprising administering a physiologically acceptable salt according to claim
 7. 